Key words: pathophysiology, diagnosis, clinical manifestation, prognosis, treatment

1. Rheumatic Fever
Prof Ariyanto Harsono MD PhD SpA(K)
1

2. INTRODUCTION
Rheumatic fever is an inflammatory
disease that occurs following
a Streptococcus
pyogenes infection, such
as streptococcal pharyngitis.
Believed to be caused byantibody
cross-reactivity that can involve
the heart, joints, skin,
and brain, the illness typically
develops two to three weeks after
a streptococcal infection. Acute
rheumatic fever commonly
appears in children between the
ages of 6 and 15, with only 20% of
first-time attacks occurring in
adults. The illness is so named
because of its similarity in
presentation to rheumatism.
Prof Ariyanto Harsono MD PhD SpA(K) 2

3. Believed to be caused by antibody cross-reactivity
that can involve the heart, joints, skin, and
brain, the illness typically develops two to three
weeks after a streptococcal infection. Acute
rheumatic fever commonly appears in children
between the ages of 6 and 15, with only 20% of first-time
attacks occurring in adults. The illness is so
named because of its similarity in presentation to
rheumatism.
prof Ariyanto Harsono MD PhD SpA(K) 3

4. Epidemiology
In developing countries, the magnitude of
ARF is enormous. Recent estimates
suggest that 15.6 million people
worldwide have rheumatic heart disease
and that 470,000 new cases of rheumatic
fever (approximately 60% of whom will
develop rheumatic heart disease) occur
annually, with 230,000 deaths resulting
from its complications. Almost all of this
toll occurs in the developing world.
The incidence rate of rheumatic fever is
as high as 50 cases per 100,000 children
in many areas. Areas of hyperendemicity
(eg, indigenous populations of Australia
and New Zealand) see an incidence of
300-500 cases per 100,000 children, while
the rates are approximately 50-fold lower
in their nonindigenous compatriots.
Rheumatic fever in the 21st century
appears to be largely a disease of
crowding and poverty.
Prof Ariyanto Harsono MD PhD SpA(K) 4

5. Diagnosis
Rheumatic heart disease at autopsy with characteristic
findings (thickened mitral valve, thickened chorda
tendineae, hypertrophied left ventricular myocardium).
Modified Jones criteria were first published in 1944 by T.
Duckett Jones, MD. They have been periodically revised
by the American Heart Association in collaboration with
other groups. According to revised Jones criteria, the
diagnosis of rheumatic fever can be made when:
two of the major criteria, or
one major criterion plus two minor criteria, are
present
along with evidence of streptococcal infection:
elevated or rising antistreptolysin O titre or DNAase.
prof Ariyanto Harsono MD PhD SpA(K) 5

6. Exceptions are chorea and indolent carditis, each of
which by itself can indicate rheumatic fever. E & D
studies have identified subclinical carditis in
patients with acute rheumatic fever, as well as in
follow-ups of rheumatic heart disease patients
who initially presented as having isolated cases of
Sydenham's chorea.
prof Ariyanto Harsono MD PhD SpA(K) 6

7. Major criteria
1. Polyarthritis: A temporary migrating inflammation of the large joints,
usually starting in the legs and migrating upwards.
2. Carditis: Inflammation of the heart muscle (myocarditis) which can
manifest as congestive heart failure with shortness of breath,
pericarditis with a rub, or a new heart murmur.
3. Subcutaneous nodules: Painless, firm collections of collagen fibers over
bones or tendons. They commonly appear on the back of the wrist, the
outside elbow, and the front of the knees.
4. Erythema marginatum: A long-lasting reddish rash that begins on the
trunk or arms as macules, which spread outward and clear in the middle
to form rings, which continue to spread and coalesce with other rings,
ultimately taking on a snake-like appearance. This rash typically spares
the face and is made worse with heat.
5. Sydenham’s chorea (St. Vitus' dance): A characteristic series of rapid
movements without purpose of the face and arms. This can occur very
late in the disease for at least three months from onset of infection.
prof Ariyanto Harsono MD PhD SpA(K) 7

8. prof Ariyanto Harsono MD PhD SpA(K) 8
Erythema marginatum
Sub cutaneous nodule
Sydenham’s chorea

9. Minor criteria
1. Fever of 38.2–38.9 °C
2. Arthralgia Joint pain without swelling (Cannot be
included if polyarthritis is present as a major
symptom)
3. Raised erythrocyte sedimentation rate or CRP
4. Leukocytosis
5. ECG showing features of heart block, such as a
prolonged PR interval (Cannot be included if
carditis is present as a major symptom)
6. Previous episode of rheumatic fever or inactive
heart disease prof Ariyanto Harsono MD PhD SpA(K) 9

10. Other signs and symptoms
1. Abdominal pain
2. Nose bleeds
3. Preceding streptococcal infection: recent scarlet
fever, raised antistreptolysin O or other
streptococcal antibody titre, or positive throat
culture.
prof Ariyanto Harsono MD PhD SpA(K) 10

11. Prof Ariyanto Harsono MD PhD SpA(K) 11

12. Pathophysiology
Rheumatic fever is a systemic disease affecting the peri-arteriolar
connective tissue and can occur after an untreated
Group A Beta hemolytic streptococcal pharyngeal infection. It
is believed to be caused by antibody cross-reactivity. This
cross-reactivity is a Type II hypersensitivity reaction and is
termed molecular mimicry. Usually, self reactive B cells remain
anergic in the periphery without T cell co-stimulation. During
a Streptococcus infection, mature antigen presenting cells
such as B cells present the bacterial antigen to CD4-T cells
which differentiate into helper T2 cells. Helper T2 cells
subsequently activate the B cells to become plasma cells and
induce the production of antibodies against the cell wall of
Streptococcus. However the antibodies may also react against
the myocardium and joints, producing the symptoms of
rheumatic fever.
prof Ariyanto Harsono MD PhD SpA(K) 12

13. prof Ariyanto Harsono MD PhD SpA(K) 13

14. Group A Streptococcus pyogenes has a cell
wall composed of branched polymers which
sometimes contain M protein that are highly
antigenic. The antibodies which the immune system
generates against the M protein may cross react with
cardiac myofiber protein myosin, heart muscle
glycogen and smooth muscle cells of arteries,
inducing cytokine release and tissue destruction.
However, the only proven cross reaction is with
perivascular connective tissue. This inflammation
occurs through direct attachment of complement
and Fc receptor-mediated recruitment of neutrophils
and macrophages.
prof Ariyanto Harsono MD PhD SpA(K) 14

15. Characteristic Aschoff bodies,
composed of swollen eosinophilic
collagen surrounded by
lymphocytes and macrophages
can be seen on light microscopy.
The larger macrophages may
become Anitschkow cells or
Aschoff giant cells.
Acute rheumatic valvular lesions
may also involve a cell-mediated
immunity reaction as these
lesions predominantly contain
Thelper cells and macrophages.
Micrograph showing an Aschoff body (right of
image), as seen in rheumatic heart disease.
prof Ariyanto Harsono MD PhD SpA(K) 15

16. In acute rheumatic fever, these lesions
can be found in any layer of the heart
and is hence called pancarditis. The
inflammation may cause a
serofibrinous pericardial exudate
described as "bread-and-butter“
pericarditis, which usually resolves
without sequelae. Involvement of the
endocardium typically results in
fibrinoid necrosis and verrucae
formation along the lines of closure of
the left-sided heart valves. Warty
projections arise from the deposition,
while subendocardial lesions may
induce irregular thickenings called
MacCallum plaques.
prof Ariyanto Harsono MD PhD SpA(K) 16

17. Rheumatic heart disease
Chronic rheumatic heart disease (RHD) is
characterized by repeated inflammation with
fibrinous repair. The cardinal anatomic changes of
the valve include leaflet thickening, commissural
fusion, and shortening and thickening of the
tendinous cords. It is caused by an autoimmune
reaction to Group A β-hemolytic streptococci (GAS)
that results in valvular damage. Fibrosis and scarring
of valve leaflets, commisures and cusps leads to
abnormalities that can result in valve stenosis or
regurgitation.
prof Ariyanto Harsono MD PhD SpA(K) 17

18. The inflammation caused by rheumatic fever,
usually during childhood, is referred to as rheumatic
valvulitis. About half of patients with acute
rheumatic fever develop inflammation involving
valvular endothelium. The majority of morbidity
and mortality associated with rheumatic fever is
caused by its destructive effects on cardiac valve
tissue. The pathogenesis of RHD is complex and not
fully understood, but it is known to involve
molecular mimicry and genetic predisposition that
lead to autoimmune reactions.
prof Ariyanto Harsono MD PhD SpA(K) 18

19. Molecular mimicry occurs when epitopes are shared
between host antigens and GAS antigens. This causes
an autoimmune reaction against native tissues in the
heart that are incorrectly recognized as "foreign" due to
the cross-reactivity of antibodies generated as a result
of epitope sharing. The valvular endothelium is a
prominent site of lymphocyte-induced damage. CD4+ T
cells are the major effectors of heart tissue
autoimmune reactions in RHD. Normally, T cell
activation is triggered by the presentation of GAS
antigens. In RHD, molecular mimicry results in incorrect
T cell activation, and these T lymphocytes can go on to
activate B cells, which will begin to produce self-antigen-
specific antibodies.
prof Ariyanto Harsono MD PhD SpA(K) 19

20. This leads to an immune response attack mounted
against tissues in the heart that have been
misidentified as pathogens. Rheumatic valves
display increased expression of VCAM-1, a protein
that mediates the adhesion of lymphocytes. Self-antigen-
specific antibodies generated via molecular
mimicry between human proteins and GAS antigens
up-regulate VCAM-1 after binding to the valvular
endothelium. This leads to the inflammation and
valve scarring observed in rheumatic valvulitis,
mainly due to CD4+ T cell infiltration.
prof Ariyanto Harsono MD PhD SpA(K) 20

21. While the mechanisms of genetic predisposition remain
unclear, a few genetic factors have been found to increase
susceptibility to autoimmune reactions in RHD. The dominant
contributors are a component of MHC class II molecules, found
on lymphocytes and antigen-presenting cells, specifically the
DR and DQ alleles on human human chromosome 6. Certain
allele combinations appear to increase RHD autoimmune
susceptibility. HLA class II allele DR7 is most often associated
with RHD, and its combination with certain DQ alleles is
seemingly associated with the development of valvular
lesions. The mechanism by which MHC class II molecules
increase a host's susceptibility to autoimmune reactions in RHD
is unknown, but it is likely related to the role HLA molecules
play in presenting antigens to T cell receptors, thus triggering
an immune response. Also found on human chromosome 6 is
the cytokine TNF-a which is also associated with RHD.
prof Ariyanto Harsono MD PhD SpA(K) 21

22. High expression levels of TNF-α may exacerbate
valvular tissue inflammation, contributing to RHD
pathogenesis. Mannose-binding lectin (MBL) is an
inflammatory protein involved in pathogen recognition.
Different variants of MBL2 gene regions are associated
in RHD. RHD-induced mitral valve stenosis has been
associated with MBL2 alleles encoding for high
production of MBL. Aortic valve regurgitation in RHD
patients has been associated with different MBL2
alleles that encode for low production of MBL. Other
genes are also being investigated to better understand
the complexity of autoimmune reactions that occur in
RHD.
prof Ariyanto Harsono MD PhD SpA(K) 22

23. Clinical Manifestations
Rheumatic fever manifests as various signs and symptoms that may
occur alone or in various combinations.
 Sore throat: Although estimates vary, only 35%-60% of patients
with rheumatic fever recall having any upper respiratory
symptoms in the preceding several weeks. Many symptomatic
individuals do not seek medical attention, go undiagnosed, or do
not take the prescribed antibiotic for acute rheumatic fever
(ARF) prevention. If a course of penicillin or another appropriate
antibiotic is taken at this time, the risk of ARF is reduced by
approximately 80%.
 Polyarthritis: Overall, arthritis occurs in approximately 75% of
first attacks of ARF. The likelihood increases with the age of the
patient, and arthritis is a major manifestation of ARF in 92% of
adults.[11]
Prof Ariyanto Harsono MD PhD SpA(K) 23

24. Carditis: Of first attacks of ARF, carditis occurs in
30%-60% of cases. It is more common in younger
children but does occur in adults.
Severe inflammation can cause congestive heart
failure (CHF).
Patients with carditis may present with shortness of
breath, dyspnea upon exertion, cough, paroxysmal
nocturnal dyspnea, chest pain, and/or orthopnea.
Carditis may also be asymptomatic and may be
diagnosed solely by auscultation or, perhaps,
echocardiography (controversial; see Physical).
Prof Ariyanto Harsono MD PhD SpA(K) 24

25.  Sydenham chorea: This occurs in up to
25% of ARF cases in children but is
very rare in adults. It is more common
in girls. Sydenham chorea in ARF is
likely due to molecular mimicry, with
autoantibodies reacting with brain
ganglioside.
 Sydenham chorea may occur with other
symptoms or as an isolated finding. It
typically presents 1-6 months after the
precipitating streptococcal infection and
usually has both neurologic and
psychological features.
 In the isolated form, laboratory evidence
of a preceding streptococcal infection
may be lacking.
 Like the polyarthritis, Sydenham chorea
usually resolves without permanent
damage but occasionally lasts 2-3 years
and be a major problem for the patient
and her family.
Prof Ariyanto Harsono MD PhD SpA(K) 25

26.  Erythema marginatum: In first
attacks of ARF in children,
erythema marginatum occurs in
approximately 10%. Like
chorea, it is very rare in adults.
 Patients or parents may report a
nonpruritic, painless, serpiginous,
erythematous eruption on the
trunk. It is usually noted only in
fair–skinned patients.
 The lesions may persist
intermittently for weeks to
months.
Prof Ariyanto Harsono MD PhD SpA(K) 26

27.  Subcutaneous nodules
 Subcutaneous nodules are
uncommon and are usually
associated with severe carditis.
They tend to occur several weeks
after illness onset, are usually
painless, and usually go unnoticed
by the patient.
 They are found primarily over the
bony surfaces or prominences and
in tendon sheaths. The common
sites include the elbows, knees,
wrists, ankles, over the Achilles
tendon, the back of the scalp, and
spinous process of the vertebrae.[2]
 They usually persist for 1-2
weeks. The main differential
diagnosis is the nodules of
rheumatoid arthritis.
Prof Ariyanto Harsono MD PhD SpA(K) 27

28. Treatment
The management of acute rheumatic fever is geared
toward the reduction of inflammation with anti-inflammatory
medications such as aspirin or
corticosteroids. Individuals with positive cultures for
strep throat should also be treated with antibiotics.
Aspirin is the drug of choice and should be given at high
doses of 100 mg/kg/day. One should watch for side
effects like gastritis and salisylate poisoning. In children
and teenagers, the use of aspirin and aspirin-containing
products can be associated with Reye’s syndrome, a
serious and potentially deadly condition. The risks,
benefits and alternative treatments must always be
considered when administering aspirin and aspirin-containing
products in children and teenagers.
prof Ariyanto Harsono MD PhD SpA(K) 28

29. Ibuprofen for pain and discomfort and corticosteroids for
moderate to severe inflammatory reactions manifested by
rheumatic fever should be considered in children and
teenagers.
Steroids are reserved for cases where there is evidence of
involvement of heart. The use of steroids may prevent further
scarring of tissue and may prevent development of sequelae
such as mitral stenosis.
Monthly injections of longacting penicillin 600.000-1.200.000
U must be given for a period of five years in patients having
one attack of rheumatic fever. If there is evidence of carditis,
the length of therapy may be up to 40 years.
Another important cornerstone in treating rheumatic fever
includes the continual use of low-dose antibiotics (such as
penicillin, sulfadiazine, or erythromycin 250 mg two times per
day) to prevent recurrence.
prof Ariyanto Harsono MD PhD SpA(K) 29

30. Vaccine
No vaccines are currently available to protect
against S. pyogenes infection, although there has
been research into the development of one.
Difficulties in developing a vaccine include the wide
variety of strains of S. pyogenes present in the
environment and the large amount of time and
people that will be needed for appropriate trials for
safety and efficacy of the vaccine.
prof Ariyanto Harsono MD PhD SpA(K) 30

31. Infection
Patients with positive cultures for Streptococcus
pyogenes should be treated with penicillin as long
as allergy is not present. This treatment will not
alter the course of the acute disease.
The most appropriate treatment for rheumatic fever
is benzathinebenzylpenicillin 600.000-1.200.000 U.
prof Ariyanto Harsono MD PhD SpA(K) 31

32. Heart failure
Inflammation
Patients with significant symptoms may require
corticosteroids. Salicylates are useful for pain.
Some patients develop significant carditis which
manifests as congestive heart failure. This requires
the usual treatment for heart failure: ACE inhibitors,
diuretics, beta blockers, and digoxin. Unlike normal
heart failure, rheumatic heart failure responds well
to corticosteroids.
prof Ariyanto Harsono MD PhD SpA(K) 32

33. Rheumatic fever primarily affects children between
ages 5 and 17 years and occurs approximately 20 days
after strep throat. In up to a third of cases, the
underlying strep infection may not have caused any
symptoms.
The rate of development of rheumatic fever in
individuals with untreated strep infection is estimated
to be 3%. The incidence of recurrence with a
subsequent untreated infection is substantially greater
(about 50%). The rate of development is far lower in
individuals who have received antibiotic treatment.
Persons who have suffered a case of rheumatic fever
have a tendency to develop flare-ups with repeated
strep infections.
prof Ariyanto Harsono MD PhD SpA(K) 33

34. The recurrence of rheumatic fever is relatively
common in the absence of maintenance of low dose
antibiotics, especially during the first three to five
years after the first episode. Heart complications
may be long-term and severe, particularly if valves
are involved.
Survivors of rheumatic fever often have to take
penicillin to prevent streptococcal infection which
could possibly lead to another case of rheumatic
fever that could prove fatal.
prof Ariyanto Harsono MD PhD SpA(K) 34

35. Prevention
Prevention of recurrence is achieved by eradicating
the acute infection and prophylaxis with antibiotics.
The American Heart Association suggests that
dental health be maintained, and that people with
a history of bacterial endocarditis, a heart
transplant, artificial heart valves, or "some types of
congenital heart defects" may wish to consider
long-term antibiotic prophylaxis.
prof Ariyanto Harsono MD PhD SpA(K) 35

36. Reference
Wallace MR. Editor: Bronze MS. Rheumatic
Fever.http://emedicine.medscape.com/article/236582-
followup#a2649
Accessed Nov 19 2014
Khan ZZ, Bronze MS (ed): Group A Streptococcus Infection.
http://emedicine.medscape.com/article/228936-overview
Accessed Nov 13 2014.
Rheumatic Fever.
http://en.wikipedia.org/wiki/Rheumatic_fever
Accessed Nov 13 2014.
prof Ariyanto Harsono MD PhD SpA(K) 36