Clin Rheumatol (2014) 33:893–901
DOI 10.1007/s10067-014-2698-8
REVIEW ARTICLE
Acute rheumatic fever and streptococci: the quintessential
pathogenic trigger of autoimmunity
Soumya D. Chakravarty & John B. Zabriskie &
Allan Gibofsky
Received: 22 May 2014 / Accepted: 23 May 2014 / Published online: 4 June 2014
# Clinical Rheumatology 2014
Abstract Acute rheumatic fever (ARF) is a non-suppurative
complication of pharyngeal infection with group A strepto-
coccus. Signs and symptoms of ARF develop 2 to 3 weeks
following pharyngitis and include arthritis, carditis, chorea,
subcutaneous nodules, and erythema marginatum. In devel-
oping areas of the world, ARF and rheumatic heart disease are
estimated to affect nearly 20 million people and remain
leading causes of cardiovascular death during the first
five decades of life. ARF still represents one of the quin-
tessential examples of a pathogenic trigger culminating in
autoimmune manifestations. In this review, we will focus on
the pathogenesis and etiology of ARF and its complications,
along with diagnostic and treatment approaches to both ame-
liorate and prevent long-term sequelae of this potentially
debilitating disease.
Keywords Autoimmunity . Group A streptococcus .
Inflammation . Microbiome . Molecular mimicry . Rheumatic
heart disease
Introduction
Acute rheumatic fever (ARF) is a delayed, non-suppurative
sequela of a pharyngeal infection with group A streptococcus
(GAS). Following the initial pharyngitis, a latent period
of 2 to 3 weeks occurs before the first signs or symptoms of
S. D. Chakravarty : A. Gibofsky (*)
Division of Rheumatology, Hospital for Special Surgery and
Department of Medicine, New York Presbyterian Hospital—Weill
Cornell Medical Center, 535 E. 70th St, New York, NY, USA
e-mail: GibofskyA@hss.edu
J. B. Zabriskie
Laboratory of Clinical Microbiology and Immunology, Rockefeller
University, New York, NY 10021, USA
ARF appear. Its manifestations may be varied and can
include arthritis, carditis, chorea, subcutaneous nodules,
and erythema marginatum. Notably, damage to cardiac
valves may be chronic and progressive, ultimately resulting
in decompensatory heart failure.
In developing areas of the world, ARF and rheumatic heart
disease are estimated to affect nearly 20 million people and
remain leading causes of cardiovascular death during the first
five decades of life [1]. Rheumatic fever can occur at any age,
but predominantly so in children 5 to 15 years of age [2–4].
Globally, there are 470,000 new cases of rheumatic fever and
233,000 deaths attributable to rheumatic fever or rheumatic
heart disease each year, with most occurring in developing
countries and among indigenous groups [5, 1]. The mean
incidence of ARF is 19 per 100,000 [6].
In the USA and other developed countries, the incidence of
ARF is much lower, with 2 to 14 cases per 100,000 and likely
due to improved hygienic standards and routine use of antibi-
otics for acute pharyngitis [7, 8]. Many cases that do occur are
usually part of localized outbreaks [9–13]. With respect to
predisposing factors, in developed countries, ARF is generally
preceded by GAS tonsillopharyngitis, but not by GAS skin
infections [14]. However, data from developing areas where
ARF and rheumatic heart disease are endemic suggest that this
association is less clear [15–17]. Among aboriginal commu-
nities of Australia, for example, the most common manifesta-
tion of GAS infection is pyoderma, with symptomatic GAS
tonsillopharyngitis and/or pharyngeal colonization being
rare [15, 16]. This could be due to the possibility that
recurrent pyoderma due to group A streptococci may afford
protection against pharyngeal colonization and infection [16].
Alternatively, group G or group C streptococci with certain
GAS antigens or enzymes may be important for the patho-
genesis of ARF [15]. Among Australian aboriginals with
ARF, group G and group C streptococci have been identified
in the throat, but not pyoderma lesions [15, 16].
894
Pathogenesis
The pathogenic mechanisms that lead to the development of
ARF remain multifactorial. It seems abundantly clear that
streptococcal pharyngeal infection is required, and genetic
susceptibility may play a salient role. Additionally, molecular
mimicry is thought to play an important role in the initiation of
tissue injury. Despite the lack of evidence for the direct in-
volvement of GAS in the affected tissues of patients with
ARF, significant epidemiologic and immunologic evidence
indirectly implicates the pathogen in disease initiation.
Outbreaks of rheumatic fever closely follow epidemics of
streptococcal pharyngitis or scarlet fever with associated phar-
yngitis [18]. Adequate treatment of a documented streptococ-
cal pharyngitis markedly reduces the incidence of subsequent
rheumatic fever [19]. Appropriate antimicrobial prophylaxis
prevents the recurrence of disease in patients who have
had ARF [20, 21]. Additionally, most patients with ARF
have elevated antibody titers to at least one of three anti-
streptococcal antibodies (streptolysin “O,” hyaluronidase,
and streptokinase), whether or not preceded by sore throat
[22].
In contrast to the high sensitivity of anti-streptococcal
antibodies for documenting streptococcal infection, isolation
of GAS from the oropharynx of patients with ARF is extreme-
ly rare, even in populations that generally do not have access
to microbial antibiotics. The clinical documentation of a pre-
ceding pharyngitis also appears to be age-related. One study,
for example, found that the recollection of pharyngitis
approached 70 % in older children and young adults versus
only 20 % in younger children [12]. Thus, a high index of
suspicion of ARF is important, particularly in children or
young adults presenting with signs of arthritis and/or carditis,
even in the absence of a documented episode of pharyngitis.
Streptococcal pharyngitis is the only streptococcal infec-
tion that has been associated with ARF. Interestingly, there
have been many documented outbreaks of impetigo that can
cause glomerulonephritis, but very rarely ARF [23, 24]. A
study of patients in Trinidad with ARF or acute glomerulone-
phritis (AGN) diagnosed during an outbreak of scabies and
secondary impetigo found that the streptococcal strains colo-
nizing the skin in patients with impetigo were different from
those associated with rheumatic fever [24]. The presence of
impetigo was associated with AGN, but not with ARF.
Bacterial genetic factors may play an important role in
determining the site of GAS infection. Five chromosome
patterns of emm genes, which code for M and M-like surface
proteins, have been recognized and labeled A–E. Pharyngeal
strains typically have patterns A–C, whereas almost all impe-
tigo strains show D and E patterns [25]. Additionally, another
factor affecting localization to the pharynx may be CD44, a
hyaluronic acid binding protein that appears to act as a pha-
ryngeal receptor for GAS. After intranasal inoculation, GAS
Clin Rheumatol (2014) 33:893–901
colonize the oropharynx in wild-type mice but not transgenic
mice that lack CD44 expression [26].
A comprehensive explanation for why ARF is only asso-
ciated with streptococcal pharyngitis remains elusive. GAS
fall into two main classes based upon differences in the C
repeat regions of the M protein [27]. One class is associated
with streptococcal pharyngeal infection, and the other (with
some exceptions) belongs to strains commonly associated
with impetigo. Thus, the particular strain of streptococcus
may be crucial in initiating the disease process. The pharyn-
geal site of infection, with its large repository of lymphoid
tissue, also may be important in the initiation of the abnormal
host immune response to those antigens cross-reactive with
target organs. Importantly, impetigo strains do colonize the
pharynx. However, they do not appear to elicit as strong an
immunologic response to the M protein moiety as the pharyn-
geal strains [28, 29]. This observation may prove to be an
important factor, especially in light of the known cross-
reaction between various streptococcal structures and mam-
malian proteins.
Molecular mimicry
Antibodies directed against GAS antigens cross-react with
host antigens [30–34]. In addition to humoral immunity, ob-
servations suggest a role for cell-mediated immunity as well in
mediating molecular mimicry found in ARF. A study of
human heart intra-lesional T cell clones found that 63 % of
patients reacted with meromyosin [35]. Furthermore, many of
these clones cross-reacted with myosin, valve-derived pro-
teins, as well as streptococcal M5 peptides. In particular,
streptococcal M protein and N-acetyl-beta-D-glucosamine
(NABG, the immunodominant carbohydrate antigen of
GAS) share epitopes with myosin [30, 32, 33]. Rodents im-
munized with recombinant streptococcal M protein type 6
develop both valvulitis and focal cardiac myositis [36]. The
potential clinical significance of these observations has been
illustrated in a study in which monoclonal antibodies were
generated from tonsillar or peripheral blood lymphocytes of
patients infected with GAS [31]. Some of these antibodies
cross-reacted with myosin and certain other proteins. In addi-
tion, anti-myosin antibodies purified from patients with ARF
cross-reacted with GAS and M protein. Similar antibodies
were present in much lower concentrations in some normal
subjects. In another study, a monoclonal antibody isolated
from a patient with rheumatic carditis was directed against
myosin and NABG [33]. The antibody was cytotoxic for
human endothelial cell lines and reacted with human valvular
endothelium, but this reactivity was inhibited by myosin, and
to a lesser extent, laminin, and NABG. The reactivity with the
extracellular matrix protein laminin may explain the reactivity
against the valve surface.
894
Pathogenesis
The pathogenic mechanisms that lead to the development of
ARF remain multifactorial. It seems abundantly clear that
streptococcal pharyngeal infection is required, and genetic
susceptibility may play a salient role. Additionally, molecular
mimicry is thought to play an important role in the initiation of
tissue injury. Despite the lack of evidence for the direct in-
volvement of GAS in the affected tissues of patients with
ARF, significant epidemiologic and immunologic evidence
indirectly implicates the pathogen in disease initiation.
Outbreaks of rheumatic fever closely follow epidemics of
streptococcal pharyngitis or scarlet fever with associated phar-
yngitis [18]. Adequate treatment of a documented streptococ-
cal pharyngitis markedly reduces the incidence of subsequent
rheumatic fever [19]. Appropriate antimicrobial prophylaxis
prevents the recurrence of disease in patients who have
had ARF [20, 21]. Additionally, most patients with ARF
have elevated antibody titers to at least one of three anti-
streptococcal antibodies (streptolysin “O,” hyaluronidase,
and streptokinase), whether or not preceded by sore throat
[22].
In contrast to the high sensitivity of anti-streptococcal
antibodies for documenting streptococcal infection, isolation
of GAS from the oropharynx of patients with ARF is extreme-
ly rare, even in populations that generally do not have access
to microbial antibiotics. The clinical documentation of a pre-
ceding pharyngitis also appears to be age-related. One study,
for example, found that the recollection of pharyngitis
approached 70 % in older children and young adults versus
only 20 % in younger children [12]. Thus, a high index of
suspicion of ARF is important, particularly in children or
young adults presenting with signs of arthritis and/or carditis,
even in the absence of a documented episode of pharyngitis.
Streptococcal pharyngitis is the only streptococcal infec-
tion that has been associated with ARF. Interestingly, there
have been many documented outbreaks of impetigo that can
cause glomerulonephritis, but very rarely ARF [23, 24]. A
study of patients in Trinidad with ARF or acute glomerulone-
phritis (AGN) diagnosed during an outbreak of scabies and
secondary impetigo found that the streptococcal strains colo-
nizing the skin in patients with impetigo were different from
those associated with rheumatic fever [24]. The presence of
impetigo was associated with AGN, but not with ARF.
Bacterial genetic factors may play an important role in
determining the site of GAS infection. Five chromosome
patterns of emm genes, which code for M and M-like surface
proteins, have been recognized and labeled A–E. Pharyngeal
strains typically have patterns A–C, whereas almost all impe-
tigo strains show D and E patterns [25]. Additionally, another
factor affecting localization to the pharynx may be CD44, a
hyaluronic acid binding protein that appears to act as a pha-
ryngeal receptor for GAS. After intranasal inoculation, GAS
Clin Rheumatol (2014) 33:893–901
colonize the oropharynx in wild-type mice but not transgenic
mice that lack CD44 expression [26].
A comprehensive explanation for why ARF is only asso-
ciated with streptococcal pharyngitis remains elusive. GAS
fall into two main classes based upon differences in the C
repeat regions of the M protein [27]. One class is associated
with streptococcal pharyngeal infection, and the other (with
some exceptions) belongs to strains commonly associated
with impetigo. Thus, the particular strain of streptococcus
may be crucial in initiating the disease process. The pharyn-
geal site of infection, with its large repository of lymphoid
tissue, also may be important in the initiation of the abnormal
host immune response to those antigens cross-reactive with
target organs. Importantly, impetigo strains do colonize the
pharynx. However, they do not appear to elicit as strong an
immunologic response to the M protein moiety as the pharyn-
geal strains [28, 29]. This observation may prove to be an
important factor, especially in light of the known cross-
reaction between various streptococcal structures and mam-
malian proteins.
Molecular mimicry
Antibodies directed against GAS antigens cross-react with
host antigens [30–34]. In addition to humoral immunity, ob-
servations suggest a role for cell-mediated immunity as well in
mediating molecular mimicry found in ARF. A study of
human heart intra-lesional T cell clones found that 63 % of
patients reacted with meromyosin [35]. Furthermore, many of
these clones cross-reacted with myosin, valve-derived pro-
teins, as well as streptococcal M5 peptides. In particular,
streptococcal M protein and N-acetyl-beta-D-glucosamine
(NABG, the immunodominant carbohydrate antigen of
GAS) share epitopes with myosin [30, 32, 33]. Rodents im-
munized with recombinant streptococcal M protein type 6
develop both valvulitis and focal cardiac myositis [36]. The
potential clinical significance of these observations has been
illustrated in a study in which monoclonal antibodies were
generated from tonsillar or peripheral blood lymphocytes of
patients infected with GAS [31]. Some of these antibodies
cross-reacted with myosin and certain other proteins. In addi-
tion, anti-myosin antibodies purified from patients with ARF
cross-reacted with GAS and M protein. Similar antibodies
were present in much lower concentrations in some normal
subjects. In another study, a monoclonal antibody isolated
from a patient with rheumatic carditis was directed against
myosin and NABG [33]. The antibody was cytotoxic for
human endothelial cell lines and reacted with human valvular
endothelium, but this reactivity was inhibited by myosin, and
to a lesser extent, laminin, and NABG. The reactivity with the
extracellular matrix protein laminin may explain the reactivity
against the valve surface.
Clin Rheumatol (2014) 33:893–901
Molecular mimicry may also be involved in the develop-
ment of Sydenham chorea. In an animal model, monoclonal
antibodies that caused chorea bound to both NABG and
mammalian lysoganglioside [37]. Exposure of cultured
human neuronal cells to either monoclonal antibodies
or serum from patients with chorea led to induction of
calcium/calmodulin protein kinase. In contrast, exposure
to serum from patients following streptococcal infection that
was not complicated by chorea did not have this effect on
neuronal cells.
Host genetic factors
Several studies have reported genetic associations with ARF,
with some appearing to be major histocompatibility complex
(MHC)-related, while others non-MHC-related. Using
alloserum from a multiparous donor, an increased frequency
of a B cell alloantigen that was not MHC-related was reported
in several genetically distinct and ethnically diverse popula-
tions of individuals with ARF [38]. In a separate study, mono-
clonal antibodies were generated by immunizing mice with B
cells from patients with rheumatic fever. One of these anti-
bodies, D8/17, was found to identify a marker expressed on
increased numbers (>20 %) of B cells in 100 % of patients
with ARF of diverse ethnic origins [39]. Conversely, the
percentage of D8/17+ B cells ranged from 4 to 6 % in 90 to
95 % of non-affected normal controls. Thus, this marker might
identify a population of rheumatic fever-susceptible individ-
uals. Interestingly, the antigen defined by this monoclonal
antibody showed no association with or linkage to any known
MHC allele, nor did it appear to be related to B cell activation
antigens. In contrast, an increased frequency of MHC class II
alleles, HLA-DR4 and DR2, has been noted in Caucasian and
black patients with rheumatic heart disease [40]. Other studies
have implicated DR1 and DRW6 as susceptibility factors in
South African black patients with rheumatic heart disease, and
a close association with HLA-DR7 and DW53 has been noted
in ARF patients in Brazil [41, 42].
These apparently disparate findings suggest that suscepti-
bility to ARF is polygenic. Consequently, the D8/17 antigen
might be associated with only one of the genes conferring
susceptibility, whereas another might be the MHC encoding
for DR antigens. Although the exact explanation remains to be
determined, the presence of an increased percentage of D8/
17+ B cells appears to identify a population at special risk of
contracting ARF.
Clinical manifestations
ARF occurs most frequently in children 5 to 15 years of age
and is rare among children 3 years old or younger and adults.
The diagnosis of ARF is largely a clinical one, and the initial
895
description of clinical manifestations, known as the Jones
criteria, was first published in 1944 and revised in 1965
[43]. Subsequently, the American Heart Association (AHA)
established guidelines for the diagnosis of rheumatic fever in
1992, and the Jones Criteria Working Group of the AHA
updated this document in 2002 [14, 44]. ARF is characterized
by GAS infection followed by clinical manifestations as
outlined in Table 1. The probability of ARF is high in the
setting of GAS infection when two major manifestations or
one major and two minor manifestations are observed [14,
44]. Two minor manifestations are not diagnostic, with
follow-up of such patients demonstrating no delayed onset
of ARF. There are three circumstances in which a presumptive
diagnosis of ARF can be made without strict adherence to the
above criteria: (i) chorea as the only manifestation, (ii) indo-
lent carditis as the only manifestation in patients who come to
medical attention months after acute GAS infection, and (iii)
recurrent rheumatic fever in patients with a history of rheu-
matic fever or rheumatic heart disease [14]. Notably, in the
absence of pericarditis or acute valvular involvement, it may
be challenging to establish a diagnosis of carditis during an
acute attack. Hence, a presumptive diagnosis of recurrent
ARF may be warranted with one major or two minor criteria
if there is evidence of a recent GAS infection.
Arthritis
The natural history of arthritis due to rheumatic fever consists
of inflammation affecting several joints in quick succession,
each lasting for a few days to a week [45]. The knees, ankles,
elbows, and wrists are affected most commonly, with the
former typically involved first. The onset of arthritis in differ-
ent joints usually overlaps, giving a characteristic migratory
pattern and thereby providing the classic description of
polyarthritis of rheumatic fever. Onset and resolution of ar-
thritis may be rapid (within 1 to 2 days), and the arthritis may
Table 1 Major and minor clinical manifestations of ARF (adapted from
reference [14])
Five major manifestations:
Migratory arthritis (predominantly involving the large joints)
Carditis and valvulitis (e.g., pancarditis)
Central nervous system involvement (e.g., Sydenham chorea)
Erythema marginatum
Subcutaneous nodules
Four minor manifestations:
Arthralgia
Fever
Elevated acute-phase reactants (erythrocyte sedimentation rate [ESR],
C-reactive protein [CRP])
Prolonged PR interval
896
be severe enough to restrict movement. Joint involvement is
more common and more severe in teenagers and young adults
than in children [46]. Though arthritis usually is the earliest
symptomatic manifestation of ARF, asymptomatic carditis
may develop first. Joint pain usually is more prominent than
objective signs of inflammation and is almost always tran-
sient. Radiographs of an affected joint may demonstrate a
slight effusion but are usually unremarkable. Analysis of the
synovial fluid in rheumatic fever with arthritis generally
demonstrates sterile inflammatory fluid.
Carditis and Sydenham chorea
Rheumatic fever may cause pancarditis, affecting the pericar-
dium, epicardium, myocardium, and endocardium. The pres-
ence of valvulitis is established by auscultatory findings to-
gether with echocardiographic evidence of mitral or aortic
regurgitation. However, echocardiography findings may be
non-specific. Sydenham chorea (also known as chorea minor
or “St. Vitus dance”) is a neurologic disorder consisting of
abrupt, non-rhythmic involuntary movements, muscular
weakness, and emotional disturbances [47]. Neurologic ex-
amination fails to reveal sensory losses or involvement of the
pyramidal tract. The movements frequently are more marked
on one side, are occasionally unilateral (hemichorea), and
cease during sleep. Muscle weakness is best demonstrated
by asking the patient to squeeze the examiner’s hands. The
pressure of the patient’s grip variably increases and decreases,
a phenomenon known as relapsing grip or “milkmaid’s sign.”
Diffuse hypotonia may also be present. Emotional changes
manifest with outbursts of inappropriate behavior, such as
crying and restlessness. In rare cases, psychologic manifesta-
tions are severe and can result in transient psychosis. Chorea
can present up to 8 months after streptococcal infections, with
a longer latent period than most other rheumatic manifesta-
tions [48]. Some patients with chorea have no other clinical
symptoms, but nevertheless should undergo an evaluation for
carditis with an echocardiogram.
Erythema marginatum
Erythema marginatum is an evanescent, pink or faintly red,
non-pruritic rash involving the trunk and occasionally the
limbs, but not the face [49]. The lesion extends centrifugally
with return of the skin in the center to a normal appearance.
The outer edge of the lesion is well-demarcated; the inner edge
is diffuse. The lesion is also known as “erythema annulare”
since the margin of the lesion is usually continuous, making a
ring. Individual lesions may appear, disappear, and reappear in
a matter of hours, with a hot bath or shower making them
more evident in some instances. Erythema marginatum usu-
ally occurs early in the course of ARF in patients with acute
carditis, but may persist or recur when all other manifestations
Clin Rheumatol (2014) 33:893–901
of disease have disappeared [50]. Cases have been reported in
patients with chronic carditis as well [45]. In some cases, the
lesions are first noticed late in the course of the illness or even
during convalescence.
Subcutaneous nodules
Subcutaneous nodules in ARF are firm, painless lesions rang-
ing from a few millimeters to 2 cm in size. The nodules are
usually located over a bony surface or prominence, or near
tendons (usually extensor surfaces), and are usually symmet-
ric. The overlying skin is not inflamed and usually can be
moved over the nodules [51]. The number of nodules varies
from a single lesion to a few dozen, with the average number
being three or four. Rheumatic subcutaneous nodules gener-
ally appear after the first few weeks of illness and usually in
patients with relatively severe carditis. Typically, nodules are
present for 1 or more weeks and rarely persist for more than a
month. In contrast to the nodules of rheumatoid arthritis,
nodules of ARF are smaller and more short-lived. Though
the elbows are involved most frequently in both rheumatic
fever and rheumatoid arthritis, rheumatic fever nodules occur
most commonly on the olecranon, whereas rheumatoid nod-
ules usually are found 3 to 4 cm distally. In more recent
outbreaks of ARF, nodules have been the least common
manifestation [52].
Sequelae
Rheumatic heart disease is the most severe sequelae of ARF. It
usually occurs 10 to 20 years after the original illness and is
the most common cause of acquired valvular disease in the
world [53, 54]. The mitral valve is more commonly involved
than the aortic valve. Mitral stenosis, caused by severe calci-
fication of the mitral valve, is the classic finding in rheumatic
heart disease. The incidence of rheumatic heart disease in
patients with a history of ARF is variable. Generally, valvular
damage manifesting as a murmur later in life is likely to occur
in about 50 % of patients with evidence of carditis at initial
presentation [55, 56]. A rare sequela associated with recurrent
episodes of ARF with polyarthritis is Jaccoud arthropathy, a
chronic arthropathy that involves the hands and/or feet, in
which the deformities are usually painless, correctable, and
do not cause functional impairment [57].
Diagnosis
Diagnostic evaluation includes studies to establish the diag-
nosis of GAS infection, evaluate acute-phase reactants, and
assess cardiac function. Streptococcal pharyngitis may be
diagnosed in one of the following ways: (i) positive throat
Clin Rheumatol (2014) 33:893–901
culture for group A beta-hemolytic streptococci, (ii) positive
rapid streptococcal antigen test, and/or (iii) elevated or rising
anti-streptolysin O (ASLO) antibody titer. Throat cultures are
negative in about 75 % of patients by the time manifestations
of rheumatic fever appear [14]. ASLO titers vary with age,
season, and geography [58]. Healthy children of elementary
school age can have titers of 200–300 Todd units/mL, while
asymptomatic pharyngeal strep carriers tend to have very low
titers (only slightly above detectable). Following streptococcal
pharyngitis, the antibody response peaks at 4 to 5 weeks,
which is usually during the second to third week of rheumatic
fever. Antibody titers fall off rapidly in the following months
and after 6 months have a slower decline. Hence, it may be
beneficial to collect one specimen when the diagnosis of ARF
is first suspected and another 2 weeks later.
About 80 % of patients with documented ARF demonstrate
a rise in ASLO titer, although this is not used as a measure of
rheumatic activity. A negative ASLO titer should prompt
commercial testing for other anti-streptococcal antibodies
such as anti-DNAse B (detectable for 6 to 9 months following
infection), streptokinase, and anti-hyaluronidase. About 90 %
of patients with documented ARF have positive findings if
two antigens are evaluated; about 95 % have positive findings
if three antigens are evaluated.
Acute-phase reactants, such as serum C-reactive protein
(CRP) and erythrocyte sedimentation rate (ESR) are invari-
ably elevated during ARF. CRP or ESR is useful for monitor-
ing “flares” of inflammation as treatment is tapered. A normal
result obtained a few weeks after discontinuing anti-rheumatic
therapy suggests that the course of the illness is complete
(unless chorea appears). The CRP may be more useful since
it typically normalizes over a matter of days once an episode
of acute inflammation has resolved, while the ESR may stay
elevated for up to 2 months after a transient inflammatory
stimulus. Other manifestations in ARF include a mild
normochromic, normocytic anemia of chronic inflammation.
Suppressing the inflammation usually improves the anemia,
and iron therapy generally is not indicated. Complement levels
are usually normal in ARF. In contrast, hypocomplementemia
is typically observed in the setting of post-streptococcal
glomerulonephritis.
There has been some speculation that some cases of arthri-
tis occurring after a streptococcal infection may not be caused
by ARF, but rather, post-streptococcal reactive arthritis
(PSRA) [59–63]. Several observations support the notion that
PSRA is a separate disorder [64, 65]. Firstly, the latent period
between the antecedent streptococcal infection and the onset
of migratory arthritis is shorter (1 to 2 weeks) than the 2 to
3 weeks usually seen in classic ARF. Secondly, the response
of the arthritis to aspirin and other non-steroidal medications is
poor in comparison to the dramatic response seen in classic
ARF. Next, evidence of carditis is not seen in these patients
and the severity of the arthritis is quite marked. Finally, extra-
897
articular manifestations, such as tenosynovitis and renal ab-
normalities, often are seen in these patients and acute-phase
reactants tend to be lower than in the setting of ARF.
However, the dilemma remains that these patients may in
the end actually have ARF, with the above observations being
explained by other factors. An unusual clinical course should
not be sufficient to exclude the diagnosis of ARF. Migratory
arthritis without evidence of other major Jones criteria, if
supported by two minor manifestations, should still be con-
sidered ARF, especially in children. Clearly defining this
reactive arthritis as a rheumatic fever variant has important
implications for secondary prophylactic treatment, and some
believe that PSRA is a benign condition without need for
prophylaxis [60]. In contrast, both the 1992 guidelines and
the 2002 update concluded that although the relationship
between PSRA and ARF remains unresolved, patients who
fulfill the Jones criteria should be considered to have ARF [58,
43]. For those patients who do not fulfill the Jones criteria, the
diagnosis of PSRA should be made only after excluding other
rheumatic diatheses, such as Lyme disease and rheumatoid
arthritis.
Treatment
Three major pillars of treatment exist: symptomatic relief of
acute disease manifestations, eradication of the GAS patho-
gen, and prophylaxis against future GAS infection to prevent
recurrent cardiac disease. Collectively, this is largely accom-
plished through use of antibiotic therapy, heart failure man-
agement, and anti-inflammatory therapy. Patients with ARF
should be initiated on antibiotic therapy to eradicate GAS
carrier states. Treatment should proceed as delineated for
management of streptococcal pharyngitis, whether or not phar-
yngitis is present at the time of diagnosis, as shown in Table 2.
In addition, household contacts should have throat cultures
Table 2 Treatment of GAS pharyngitis (adult dosages and regimens
shown) (adapted from reference [78])
a
Oral penicillin V—500 mg two to three times a day for 10 days
Intramuscular penicillin, single dose—penicillin G benzathine
1.2 million units
Amoxicillin—875 mg twice a day or 500 mg three times a day for
10 days
Cephalexin—500 mg twice a day for 10 days
Alternative regimens if severe hypersensitivity to beta-lactam antibiotics
exists:
Azithromycin—500 mg on day 1 followed by 250 mg daily on days 2
through 5
Clarithromycin—250 mg twice a day for 10 days
Clindamycin—450 to 600 mg orally three times daily for 10 days
a
Preferred antibiotic
898
performed, and those with positive results should also receive
a full course of antibiotic therapy, even if asymptomatic.
Patients with severe carditis (significant cardiomegaly, con-
gestive heart failure, and/or third-degree heart block) should
be treated with conventional therapy for heart failure. Valve
surgery may be necessary when heart failure due to regurgitant
lesions cannot be managed with medical therapy alone [66,
67]. Surgical outcomes are generally better if valve surgery
can be performed when carditis is quiescent [67]. Valve repair,
if feasible, is preferred over valve replacement since repair
avoids the need for long-term anticoagulation associated with
mechanical valves and the long-term risk of deterioration of a
bioprosthesis [66].
Aspirin (80 to 100 mg/kg per day in children and 4
to 8 g/day in adults) is the major anti-inflammatory agent for
relief of symptoms due to ARF. Aspirin levels can be mea-
sured, with 20 to 30 mg/dL being the therapeutic range. The
efficacy of other anti-inflammatory drugs in the setting of
active rheumatic carditis remains unclear [68, 55, 69–71]. A
meta-analysis of eight randomized trials including 996 pa-
tients with ARF found no significant difference in the risk of
cardiac disease at 1 year between the corticosteroid-treated
and aspirin-treated groups [69]. No reduction in the risk of
heart valve lesions was observed with corticosteroids or intra-
venous immunoglobulin [69]. Anti-inflammatory therapy
should be continued until all symptoms have resolved.
Normalization of inflammatory markers, such as ESR and
CRP, can be utilized as biomarkers of resolution. The rash
associated with ARF is transient and does not require any
particular treatment, although anti-histamines may alleviate
any associated pruritus.
Prevention
Prevention of initial and recurrent attacks of rheumatic fever
depends on effectively treating GAS pharyngitis [72, 10].
Prevention of an initial episode of rheumatic fever (primary
prevention) is accomplished by prompt diagnosis and antibi-
otic treatment. Appropriate antibiotic treatment of streptococ-
cal pharyngitis prevents ARF in most cases [19]. However, at
least one third of ARF episodes occur in the setting of inap-
parent streptococcal infection [73]. For secondary prevention,
patients who have had an episode of ARF and develop sub-
sequent GAS pharyngitis are at high risk for a recurrence of
rheumatic fever, with progression in severity of rheumatic
heart disease from the initial episode. The most effective
method to limit progression of rheumatic heart disease sever-
ity is prevention of recurrent GAS pharyngitis. As a conse-
quence, prevention of recurrent rheumatic fever (secondary
prevention) requires continuous antimicrobial prophylaxis,
rather than recognition and treatment of acute GAS pharyngi-
tis episodes. Continuous prophylaxis is warranted for patients
with well-documented history of rheumatic fever (including
Clin Rheumatol (2014) 33:893–901
Table 3 Risk factors for recurrent rheumatic fever (adapted from refer-
ences [68, 78])
The number of previous attacks
Time since the last attack
Risk of exposure to streptococcal infections
Patient age
Presence or absence of cardiac involvement
cases with Sydenham chorea as the sole manifestation) and
those with definite evidence of rheumatic heart disease.
Prior to initiation of prophylaxis, a full therapeutic course
of antibiotic therapy should be given to patients with ARF to
eradicate residual GAS, even if a throat culture is negative.
Prophylactic antibiotics should be initiated immediately at the
end of the therapeutic antibiotic course. During the course of
prophylaxis, patients and their household contacts who devel-
op acute episodes of GAS pharyngitis should be evaluated and
treated promptly as well. The duration of secondary preven-
tion for prevention of recurrent rheumatic fever consists of
years of administering prophylactic antibiotics, with the total
duration depending on risks for recurrent rheumatic fever and
severity of disease. The risk of recurrent rheumatic fever
depends on several factors, as outlined in Table 3. Risk is
increased among individuals with ongoing exposure to strep-
tococcal infections including children, those in close contact
with children (such as parents or health care workers), and
those living in close quarters (including college students and
military personnel, for example) [74]. Risk increases with
number of previous attacks but decreases as the interval
lengthens since the most recent attack.
The optimal duration of antibiotic prophylaxis following
ARF remains unclear. Patients who have had rheumatic
carditis (with or without valvular disease) are at relatively
high risk for recurrent carditis and are likely to sustain increas-
ingly severe cardiac involvement with each recurrence [75,
76]. Therefore, in general, prophylaxis in the setting of carditis
should continue until the patient attains young adulthood
(21 years of age), which is usually 10 years from an acute
attack with no recurrence [77, 78]. This approach was evalu-
ated in a Chilean study of 59 patients with history of ARF
Table 4 Secondary prophylaxis for rheumatic fever (adult dosages and
regimens shown) (adapted from reference [78])
a
Intramuscular penicillin every 4 weeks—penicillin G benzathine
1.2 million units
Oral penicillin V—250 mg twice a day
Sulfadiazine—1,000 mg once a day
Alternative regimen if severe hypersensitivity to beta-lactam antibiotics
exists:
Azithromycin—250 mg daily
a
Preferred antibiotic
Clin Rheumatol (2014) 33:893–901
judged to be at relatively low risk for recurrence of ARF [77].
Among patients with history of ARF without carditis, prophy-
laxis was discontinued after 5 years or at age 18 (whichever
was longer). During 3,349 patient-months of follow-up, only
two ARF recurrences were observed (0.7 per 100 patient-
years). These data suggest that ARF prophylaxis can likely
be discontinued safely in young adults judged to be at low risk
for recurrence who are maintained under careful prospective
surveillance.
Choice of antibiotics
The preferred antibiotic approach for secondary prevention of
recurrent rheumatic fever is administration of long-acting
benzathine penicillin G intramuscularly every 4 weeks (see
Table 4). A shorter dosing interval (such as administration
every 2 to 3 weeks) is appropriate for populations in which the
incidence of rheumatic fever is particularly high. This ap-
proach is also warranted for individuals in low-incidence
regions who have had recurrent ARF despite adherence to a
regimen administered every 4 weeks. In addition, the long-
term benefits of intramuscular benzathine penicillin G pro-
phylaxis outweigh the risk of an allergic reaction, as these are
rare [79]. Options for oral prophylaxis include penicillin V,
sulfadiazine, and macrolides. Success with oral prophylaxis
depends on patient adherence, so clear communication regard-
ing the importance of prophylaxis and how antibiotics should
be taken is critical. Even with optimal adherence, the risk of
recurrence is higher in individuals receiving oral prophylaxis
than those receiving intramuscular benzathine penicillin G
[80]. This was illustrated in a controlled trial of 405 patients
with rheumatic fever assigned to receive 4 weeks of intramus-
cular benzathine penicillin G, oral penicillin G, or oral sulfa-
diazine. In the first 2 years of the study, streptococcal infec-
tions recurred in 7, 20, and 24 % of patients and rheumatic
fever recurred in 0, 4.8, and 2.7 % of the patients, respectively.
Hence, parenteral prophylaxis is preferred for patients at high
risk for rheumatic fever recurrence, with oral agents being
appropriate for patients at lower risk. Consequently, switching
from intramuscular to oral prophylaxis once patients have
reached young adulthood and have remained free of rheumatic
attacks can be a viable option.
Conclusions
ARF remains one of the few autoimmune disorders known to
occur as a result of a specific pathogen. It remains a chronic
and serious consideration in many parts of the developing
world, and as a result, the importance of early diagnosis and
treatment is paramount. Though joint manifestations can be
migratory, transient, and self-limiting, cardiac sequelae have
899
the potential for being chronic and life-threatening. The recent
identification of an increased percentage of D8/17+ B cells
appearing in a cohort of individuals at special risk of
contracting ARF may provide an opportunity to identify early
on those who may benefit from any future vaccinations for
GAS that are developed, as well as increased surveillance and
early, effective antibiotic strategies. Further research into ARF
as a paradigm for microbial-induced autoimmunity via mo-
lecular mimicry has enormous ramifications for advancing the
field of autoimmunity and rheumatic diatheses in particular.
Indeed, this may provide an invaluable roadmap in further
elucidating the etiology of other inflammatory diseases in
which a potential, offending pathogenic trigger has yet to be
identified.
Conflict of interest There are no relevant conflicts to disclose by any of
the authors.
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