Autoimmunity Reviews 9 (2009) 117–123

Contents lists available at ScienceDirect

Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

Acute rheumatic fever and its consequences: A persistent threat to developing

nations in the 21st century
Jennifer L. Lee, Stanley M. Naguwa, Gurtej S. Cheema, M. Eric Gershwin ⁎
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, United States

a r t i c l e i n f o a b s t r a c t

Article history: Acute rheumatic fever (ARF) is an autoimmune, multi-system response secondary to molecular mimicry
Received 12 March 2009 following Lancefield group A streptococcus (GAS) pharyngitis; it is now most commonly found in the
Accepted 6 April 2009 pediatric populations of developing nations. The major source of morbidity and mortality of ARF stems from
Available online 19 April 2009
rheumatic heart disease (RHD), although the cardinal symptoms of the disease also include polyarthritis,
Sydenham's chorea, subcutaneous nodules, and erythema marginatum. Therapy is aimed towards treating
Keywords:
Rheumatic fever
the initial GAS infection, using anti-inflammatory medications for acute symptoms and surgery to correct
Rheumatic heart disease RHD. Secondary prevention is crucial, given the high risk of recurrence, and includes long-term antibiotic
Group A streptococcus pharyngitis prophylaxis. However, vaccination towards GAS may soon be on the horizon, which may assist in both
Sydenham's chorea decreasing the risk of initial infection in naïve patients and helping to lower the risk of recurrence.
© 2009 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
3. Pathogenesis and association with group A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
4. Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
4.1. Carditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
4.2. Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
4.3. Neuropsychiatric manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
4.4. Skin findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4.5. Presentation in children younger than 5 years of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
5.1. Post-streptococcal reactive arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
5.2. The link between ARF and other rheumatic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
6. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7. Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
8. Prognosis and predictors of disease course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
9. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
9.1. Antibiotic prophylaxis for rheumatic heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
10. Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
10.1. Primary prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
10.2. Secondary prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
10.3. Potential for vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Take-home
. messages
Take-home . .
messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

⁎ Corresponding author. Tel.: +1 530 752 2884; fax: +1 530 752 4669.
E-mail address: megershwin@ucdavis.edu (M.E. Gershwin).

1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2009.04.002
118 J.L. Lee et al. / Autoimmunity Reviews 9 (2009) 117–123

1. Introduction it is likely that numerous cases, and therefore the prevalence and
incidence, of ARF and RHD are largely underestimated.
Acute rheumatic fever (ARF) is a constellation of symptoms that A systematic review of 10 population-based studies published
stems from a nonsuppurative, auto-inflammatory multi-system from 1967 to 1996 describes the worldwide incidence of ARF [3]. The
response following infection by group A streptococcus (GAS), or highest reported annual incidence rate was 51 per 100,000 per year by
Streptococcus pyogenes. Particularly because of its chronic effects on a study conducted in northern India, with the mean incidence of all
cardiac valves, termed rheumatic heart disease (RHD), ARF continues studies at 19 per 100,000 per year. The lowest incidence rates were
to contribute a significant amount to global morbidity and mortality. found in American and Western European nations, while higher rates
In many developing countries, RHD is the most common source of are found in Eastern Europe, Asia, Australasia, and the Middle East. Of
acquired heart disease in children and young adults. The recognition note, information from Africa is not available for this study, though it is
of symptoms comprising the syndrome of ARF dates back centuries widely known that African nations have a high predominance of
ago, with Poynton and Paine initially reporting the potential link pediatric patients with RHD.
between streptococcal pharyngitis and rheumatic fever in 1900. The first episode of ARF most commonly strikes children and
Diagnosis is now centered around the 1992 updated Jones' criteria, which young adolescents, usually from ages 5–14 years old, though younger
includes carditis, polyarthritis, erythema marginatum, Sydenham's and middle-aged adults are also affected at a lower frequency. It is rare
chorea, and subcutaneous nodules, in the setting of a preceding GAS for patients to experience their initial RF episode younger than 2 years
infection. or greater than 35 years of age [2]. In a study of 541 pediatric patients
with ARF at the University of Utah by Tani et al., it was found that 5% of
these patients were younger than 5 years old at diagnosis [4].
2. Epidemiology In the United States, the number of ARF cases has fallen
dramatically over the last half century. A national study conducted
The prevalence of ARF now appears to be much higher in less in 2000 detailing the characteristics of American pediatric patients
developed countries, particularly in indigenous and less affluent areas, hospitalized with ARF found that the incidence was 14.8 cases per
and varies significantly from one region to the next (See Table 1). In 100,000 hospitalized children (though the true national incidence of
2005, it was estimated that the incidence of ARF was more than ARF cases is b1 case per 100,000 population), with the greatest
471,000 cases per year, with 336,000 cases in those 5–14 years of age. number of hospitalizations for ARF occurring in Utah, Hawaii,
The prevalence of RHD is estimated to range from 15.6 to 19.6 million Pennsylvania, and New York [5]. Patients of Asian or Pacific Island
cases worldwide, with 282,000 newly diagnosed with over 233,000 descent with ARF were also more likely to be hospitalized than those
deaths attributed to RHD each year. Unfortunately, given the disease's who were Caucasian.
predilection for children, over 2.4 million of these cases were in Concern in the 1980s had arisen over several outbreaks in several
patients aged 5–14 years old [1]. A higher incidence has been reported states including Tennessee, Ohio, and Pennsylvania. However, cases
among the aborigines of Australia, the Maoris of New Zealand, and have since decreased and are now mainly limited to Salt Lake City,
populations in sub-Saharan Africa [2]. However, given the limitations Utah. The overall decline is believed to be due to improvements in
of reports related to limited resources in many of these endemic areas, aspects of primary prevention, including access to health care and
crowding and use of antibiotics. It has also been postulated that
evolving differences in the streptococcal M protein type, the main
bacterial virulence factor to which host antibodies bind to confer
Table 1 protective immunity, has also played a role in the number of
Collective summary of the characteristics and treatment of rheumatic fever.
diminishing cases [6]. However, it still remains unclear why the
At-risk populations Clinical signs/ Diagnosis (updated Treatment trend has moved away from rheumatogenic strains of GAS to those
symptoms 1 Jones' Criteria [12]) that do not commonly lead to the development of RF.
Ethnic sub-groups Non-specific Major criteria Antibiotics
Maori (New Zealand) Fever Carditis Penicillin
3. Pathogenesis and association with group A
Aborigines (Australia) ⇧ ESR, CRP Polyarthritis Anti-
inflammatories streptococcal pharyngitis
Pacific Islanders Anemia Sydenham's chorea Salicylates
Sub-Saharan Africa Cardiac Erythema Corticosteroids ARF is believed to be a consequence of molecular mimicry, an
marginatum autoimmune phenomenon that occurs after host infection with GAS
Age groups Pancarditis Subcutaneous nodules Surgery
Ages 5 to 15 Pericarditis Minor criteria Valve repair
and involves both humoral and cellular immune responses. The
Risk Factors Myocarditis Arthralgias concept of molecular mimicry is well described elsewhere. Anti-
Low socioeconomic Arthritis Fever streptococcal antibodies are produced by B cell lymphocytes that
status cross-react with host tissue epitopes, causing inflammation in various
Overcrowding Polyarticular Elevated
organ systems. In addition, bacterial peptide fragments, many of
inflammatory markers
Limited access to medical Migratory Prolonged P–R which are similar to host proteins, are presented to T cell lymphocytes
care interval (with a prominent role by CD4+ T cells in rheumatic valvular lesions)
History of rheumatic Large joints Preceding via major histocompatibility complex (MHC) molecules, inducing an
fever (for recurrences) Streptococcal immune response [7]. Shared epitopes are located on the M protein of
infection
Neuropsychiatric Positive throat
GAS and human cardiac (especially myosin), synovial, and neuronal
cultures tissues. In Sydenham's chorea, antibodies are directed against
Sydenham's Elevated or rising ASO neuronal cells of the basal ganglia. Other similarities have been
chorea titers found between hyaluronidate located in the capsule of GAS and
OCD/ADHD
hyaluronic acid found in human synovium, as well as between N-
Tic disorders
Cutaneous acetylglucosamine in the streptococcal cell wall/capsule and in human
Erythema cardiac valves [7,8].
marginatum The development of RF is likely due to contributions from both
Subcutaneous genetic and environmental influences. An association with MHC Class
nodules
II antigens, which help to present extracellular antigens to the T cell
 J.L. Lee et al. / Autoimmunity Reviews 9 (2009) 117–123
receptor, has been found to play a key role in the pathway towards
activating the inflammatory cascade. In particular, HLA-DR7 has been
found to be important in many different ethnic populations, while
other studies have identified HLA-DR2 in African Americans and HLA-
DR4 in Caucasian-Americans. Other non-MHC proteins that may also
be influential in the autoimmune response against GAS include
mannose binding lectin (MBL) and various cytokines, such as variants
of tumor necrosis factor (TNF)-a and IL-1 [7,9].
Infection with GAS can present in a variety of ways, including
pharyngitis, post-streptococcal glomerulonephritis, impetigo, and
invasive infections, such as streptococcal toxic shock syndrome and
necrotizing fasciitis. As alluded to above, certain streptococcal strains
are more likely to lead to the development of ARF, termed
“rheumatogenic” strains; the general consensus is that these strains
are also those who are initially responsible for causing GAS
pharyngitis. In the United States, the M types most frequently
known to cause RF include serotypes 1, 3, 5, 6, 14, 18, 19, 24, 27, and
29, though one study postulated that in Hawaii (a state with one of the
highest incidences of RF in the nation), unusual serotypes not typical
for RF caused pathology [6,8,10]. Specific characteristics of these
strains have been found to cause increased virulence, including higher
M protein content and mucoid colony formation, which suggests the
presence of a large capsule that protects against phagocytosis [6,11].
4. Clinical presentation
Rheumatic fever (RF) can present with a variety of findings, with a
latency period of 2–5 weeks after the initial episode of streptococcal
pharyngitis. These symptoms can generally be categorized into
musculoskeletal, cardiac, neuropsychiatric, and integumentary com-
plaints (see Table 1). In addition, non-specific symptoms in a patient
with ARF can include fever, elevated inflammatory markers, precordial
or abdominal pain, tachycardia, malaise, anemia, and epistaxis [12].
Occasionally, episodes are asymptomatic, making it difficult to
determine in some patients the need for secondary prophylaxis.
This, unfortunately, puts them at risk for developing more severe RHD
if re-infected with GAS.
4.1. Carditis
30–45% of patients with RF exhibit carditis as a manifestation of
their disease. Carditis can encompass the spectrum from valvulitis to
myocarditis to pericarditis [12]. Most frequently, pancarditis, or
endocarditis, is seen. Initially, valvular disease involves dilatation of
the valve causing regurgitation, but chronic progression can lead to
stenosis. Cardiac involvement in RF can even extend to inflammation
in the coronary arteries, which has mainly been found on autopsy, but
does not solely meet criteria for diagnosis of carditis in ARF.
The severity of rheumatic carditis ranges widely among indi-
viduals, but often lends the most significant contribution to the
morbidity and mortality of RF. Its presentation can include such
clinical signs and symptoms as a pericardial rub, tachycardia, an apical
systolic murmur consistent with mitral regurgitation, a basal diastolic
murmur consistent with aortic regurgitation, or severe congestive
heart failure. In severe acute cases, RHD can lead to fatal consequences
despite medical therapy. Demonstrated by a case series of 3 pediatric
patients, who developed acute carditis with involvement of multiple
valves and impaired systolic dysfunction, severe carditis has been
likened to acute mitral regurgitation with the potential for rapid
deterioration [13].
Subclinical carditis, in which valvular regurgitation seen on
echocardiography does not manifest clinically as an audible murmur,
can also be seen. A systematic review of the literature published in
2007 found that the weighted pooled prevalence of reported
subclinical carditis was 16.8%, with 44.7% experiencing persistence
or deterioration of their valve lesion during a follow-up period of
119
3–23 months, though it was noted that follow-up data was of poor
quality [14]. However, even in the most recent meeting of the Jones
Criteria Workshop, the sole finding of subclinical carditis does not yet
fulfill the Jones criteria for cardiac symptoms, as it still remains
unclear with current technology which findings are physiologic versus
pathologic [15].
It has been estimated that 60% of those with ARF will develop RHD
[1]. The risk of developing RHD has been shown to directly correlate
with the severity of carditis during the initial attack. Despite regularly
administrated antibiotic prophylaxis for secondary prevention, carditis
has been reported to recur, though in many cases, recurrences are due to
poor compliance [16]. These recurrent episodes tend to mimic the initial
attack, and generally occur within the first 5 years.
4.2. Arthritis
Arthritis is likely the most common symptom of RF, occurring in
60–80% of patients, and is often the first presentation of the disease
[8]. It is most frequently polyarticular, migratory (with episodes
lasting 2 to 3 days in each joint), and non-deforming. Large joints are
mostly affected, particularly the knees, ankles, elbows, and wrists.
Uncommonly, ARF can present as a monoarticular arthritis, particu-
larly in those already treated with non-steroidal anti-inflammatory
medications (NSAIDs), which can be difficult to distinguish from
septic arthritis. The duration of each arthritic attack usually lasts a
maximum of 4 weeks, and can also often mimic joint symptoms from
a viral infection [17]. Given the arthritis is non-specific, other
conditions on the differential should include reactive arthritis,
connective tissue diseases, sickle-cell disease, leukemia, and lym-
phoma [18].
Rarely, patients with chronic RF can develop Jaccoud's arthropathy,
reducible deformities of the affected joints. However, this arthropathy
is now more commonly seen in systemic lupus erythematosus (SLE)
patients who have suffered chronic, recurrent bouts of arthritis
secondary to uncontrolled or untreated inflammation.
4.3. Neuropsychiatric manifestations
Sydenham's chorea (or St. Vitus' dance), occurs in approximately
10% of patients, and is a well-known, but not exclusive, neurologic
manifestation of rheumatic fever. Chorea can also be found in a
number of conditions, including systemic lupus erythematosus,
encephalitis, Lyme disease, and drug intoxication [2]. Typical
characteristics of chorea include involuntary, purposeless, non-
rhythmic movements, usually of the face and extremities, while the
patient is awake; weakness; and emotional lability. It can also be
accompanied by frequent falls, dysarthria, and difficulties in concen-
tration [18].
In RF, chorea is most often seen in older children and young
adolescents, with a slightly higher predisposition in the female
population, and is usually found late in the disease course. In a
Turkish study of 65 patients by Demiroren et al., 78.5% had generalized
chorea, with a 37.9% rate of recurrence. 70.5% of the 61 patients that
underwent echocardiography were also found to have valvular
involvement [19]. However, chorea has been seen as an isolated
symptom of RF, and can be used to make a presumptive diagnosis with
its presence alone. Interestingly, isolated chorea usually is not
associated with elevated inflammatory markers, in contrast to other
manifestations of RF. It tends to remit with or without therapy, but
often can recur with similar symptoms [18].
A possible association between ARF and several psychiatric
conditions has also been reported in several studies, including
obsessive compulsive disorder (OCD), tic disorders, major depression,
and attention deficit hyperactivity disorder (ADHD) [18,20].
120 J.L. Lee et al. / Autoimmunity Reviews 9 (2009) 117–123
4.4. Skin findings
Cutaneous manifestations of RF tend to be very rare and are self-
limited. The classic appearance of erythema marginatum is an
evanescent, pink rash, usually found on the trunk and the extremities,
and spares the face [12]. Subcutaneous nodules are painless, and can
be found on the extensor surfaces of the wrists, elbows, knees and
ankles.
4.5. Presentation in children younger than 5 years of age
It has been postulated that the youngest patients with ARF may
present with a different clinical syndrome in contrast to their older
counterparts. In a retrospective study by Tani et al., it was found that
those children who developed RF (as diagnosed by the Jones criteria)
at an age younger than 5 years old had a higher incidence of moderate
to severe carditis, manifested by cardiomegaly with or without
congestive heart failure, but a lower likelihood of having chorea [4].
In addition, their clinical presentation was more likely to include
arthritis and erythema marginatum.
5. Diagnosis
An accurate diagnosis is imperative in any patient suspected to
have ARF, as misdiagnosis can potentially involve long-term, unnec-
essary antibiotic therapy. On the other hand, underdiagnosis, particu-
larly with milder initial presentations, can lead to unrecognized
recurrent bouts of RF that can result in significant chronic carditis. An
article by Williamson et al. addresses several such pitfalls in reaching a
diagnosis [17], including the frequent absence of a history of sore throat
in younger patients who have difficulty relaying symptoms to their
caregivers and the difficulty in recognizing and diagnosing a preceding
streptococcal infection.
To help facilitate appropriate diagnosis, criteria were initially
characterized by Dr. T. Duckett Jones in 1944, which have been revised
several times throughout the years by the American Heart Association.
The most recently updated set of criteria was set forth in 1992, and is
meant to be applied for the diagnosis of the first episode of ARF only
(See Table 1). These guidelines recommend that a practitioner initially
determines the likelihood of a preceding GAS infection [12]. To do so,
one should have a high clinical suspicion in the setting of positive
throat cultures or high or rising anti-streptolysin O (ASO) titers, given
that symptoms of ARF usually emerge concomitantly with a peak in
antibody titers. Sensitivity in detecting true streptococcal infection
increases when these two tests are used in combination with the
presence of other streptococcal antibodies, including anti-DNase B
and antihyaluronidase [21].
For a diagnosis of ARF, presenting symptoms are divided into major
and minor criteria. Major criteria include: (1) carditis, (2) polyarthritis,
(3) Sydenham's chorea, (4) erythema marginatum, and (5) subcutaneous
nodules. Minor criteria include both clinical (arthralgias and fever,
usually above 39 degrees Celsius) as well as objective aspects (ele-
vated acute phase reactants of disease, such as erythrocyte sedi-
mentation rate (ESR) or C-reactive protein (CRP), and a prolonged
P–R interval on EKG) [12]. For one to fulfill the criteria of ARF,
an individual must have two major or one major and two minor
manifestations plus a clinical setting that points towards a preced-
ing GAS infection.
The authors of the updated guidelines also state that a presumptive
diagnosis of ARF can be made in the absence of the above criteria in
the following instances: if isolated chorea is present without any other
manifestation; if longstanding carditis is seen without any other
symptom; or if, in a patient with a history of ARF or RHD, a single
major or several minor criteria are fulfilled. This latter scenario
is termed a recurrent episode of rheumatic fever, and is due to
reinfection by GAS.
In 2002, the updated Jones criteria were reviewed at the Jones
Criteria Workshop, with panel members confirming the continued
validity of the updated criteria set forth in 1992. The use of
echocardiography was recognized in visualizing rheumatic valvular
disease, but they maintained that this imaging modality should not be
used as a sole determinant of carditis in the absence of an auscultated
murmur. In addition, it was noted that a single laboratory test alone
was still unavailable to make an adequate diagnosis of ARF or its
recurrent episodes [15].
5.1. Post-streptococcal reactive arthritis
Post-streptococcal reactive arthritis (PSRA) is a known entity that
is associated with GAS infection, but it is still unclear if it is truly a
separate condition from ARF or represents a component of the same
spectrum. It, like RF, occurs after infection with GAS, and can be a
monoarticular or polyarticular arthritis, but does not exhibit the full
constellation of symptoms of RF. It also appears that, while the
arthritis found in ARF is quite responsive to salicylates, patients with
PSRA do not respond as well to treatment.
Barash et al. attempted to develop an objective approach to help
distinguish between these two diseases by retrospectively examining
159 patients with PSRA and 68 patients with ARF [22]. They found that
both groups had the same proportion of positive throat cultures for
GAS, and had similar latency periods, measured in terms of the
interval between the onset of pharyngitis and the onset of arthritis
(approximately 15 days for both). However, all patients with ARF had
carditis (while all those with PSRA did not), and there was a trend
towards a higher percentage of patients with ARF having fever N38 °C,
more active joints, and a migratory arthritis. In addition, the resolution
of arthritic symptoms was much more rapid in the patients with ARF
than with PSRA. From this information, they were able to formulate an
equation to help distinguish ARF from PSRA (with a sensitivity of 79%
and a specificity of 87.5%) using the highest predictors between the
two groups: ESR, CRP, duration of joint symptoms in response to anti-
inflammatory medications, and relapse of joint symptoms after
cessation of treatment.
5.2. The link between ARF and other rheumatic diseases
Symptoms of ARF can often mimic those of other autoimmune
diseases, particularly given the frequency of arthralgias and arthritis
seen in these patients, and it can sometimes be difficult to determine
the true underlying diagnosis. Recently, in a sample of 53 pediatric
patients in Paraguay initially diagnosed by their general practitioners
with ARF, 44.6% were actually later found to have a rheumatologic
etiology for their symptoms [23]. These diagnoses included juvenile
idiopathic arthritis, patellofemoral syndrome, SLE, and reactive
arthritis.
In addition, ARF should always remain in the differential for septic
arthritis, particularly when diagnostic arthrocentesis of a monoarticular
arthritis yields sterile synovial fluid in patients living in endemic areas. It
is also especially important to be cognizant of an abnormal cardiac
murmur in conjunction with these symptoms. In a study of 157 RF
patients by Harlan et al., 3 patients were found to have a monoarticular
arthritis with sterile synovial fluid, with all initially being treated for
septic arthritis, but were later found on follow-up to have significant
carditis, ultimately leading to a diagnosis of RF [24]. Other etiologies to
consider when faced with monoarticular arthritis in pediatric patients,
of course, are certain subsets of juvenile idiopathic arthritis and Lyme
disease.
In rare case reports, ARF has been postulated to co-exist with other
rheumatic phenomena. A series of 3 retrospective pediatric cases were
discussed by Eisenstein and Navon-Elkan in which features of
Henoch–Schonlein purpura appeared to concomitantly occur with
ARF. This continues to raise the possibility that GAS infection may
 J.L. Lee et al. / Autoimmunity Reviews 9 (2009) 117–123
contribute to the pathogenesis of both diseases, though this remains
controversial [25].
6. Pathology
Pathological examination of valves affected by RF carditis reveals
that the mitral valve is most commonly affected, followed by the
aortic, tricuspid and, uncommonly, pulmonic valve. Pathologic
findings include thickening of the valve leaflets and chordae, mitral
annular dilation, and chordal elongation [26]. Aschoff nodules are a
signature pathological finding in RF carditis, and are found most
frequently in the subendocardium. They are aggregates of cells that
originate from macrophages and histiocytes, and can be found in the
company of lymphocytes and plasma cells. The histology of sub-
cutaneous nodules reveals fibrinoid degeneration and necrosis of
collagen surrounded by mononuclear inflammatory cells [27].
7. Imaging
Echocardiography is the mainstay of diagnostic imaging for ARF,
though this is by no means a perfect modality, as it is often difficult to
distinguish healthy variant versus pathologic valvular disease by
echocardiography alone. As stated earlier, valvular disease seen
exclusively on echocardiography in the absence of an auscultated
murmur does not currently fit the criteria for diagnosing carditis. In a
recent attempt by Carapetis et al. to find an adequate screening tool
for RHD in endemic areas, auscultation was found to miss 54% of those
with RHD when confirmed with echocardiography. However, the
likelihood of finding pathology on portable echocardiography was
significantly raised if an abnormal murmur was found initially on
clinical exam [28].
8. Prognosis and predictors of disease course
If left untreated, an episode of RF tends to resolve on its own within
3 months, but can result in chronic cardiac damage. Approximately
65–75% of patients recover from an episode of carditis without any
future consequences, though the likelihood of full resolution is much
lower if carditis is severe, or of course, if recurrent episodes occur
[2,21]. Overall prognosis in RF, as a result, is largely dependent on the
degree of RHD that an individual suffers from, as this is the main cause
of morbidity and mortality in these patients. In a study by Meira et al.,
a group of children and adolescents in Brazil were followed by clinical
examination and Doppler echocardiography for a mean of 5.4 years
after their initial episode of ARF. It was found that the risk of
developing significant chronic RHD was independently associated
with moderate or severe carditis, recurrent episodes of rheumatic
fever, and a mother's low educational level [29].
9. Treatment
Treatment of RF involves a two-pronged approach, with one arm
focused on treating the streptococcal infection with antibiotics (the
drug of choice being penicillin), and the other aimed towards using
anti-inflammatory medications to treat the symptoms of RF (see
Table 1). Anti-inflammatory therapy mainly includes salicylates and
steroids, though intravenous immunoglobulin has also been reported
to be used in carditis. Recommended doses for salicylates are 80–
100 mg/kg/day for children and 4–8 g/day for adults for 2 weeks, then
decreased to 60–70 mg/kg/day for an additional 3–6 weeks. Pre-
dnisone, the preferred steroid, is usually dosed initially at 1–2 mg/kg/
day, with a maximum of 80 mg/day, and then tapered after 2–3 weeks
by 20–25% each week [21].
In rheumatic carditis, most practitioners tend to use steroids for
severe disease (including congestive heart failure, significant valvular
disease, and pericarditis), while salicylates are usually reserved for
121
milder presentations. ARF is an autoimmune disease that requires a
multi-discipline effort [30,31]. Caution must be used with either
therapy alone, as rebound can be seen with steroids and relapse with
salicylates. Treatment duration usually lasts over a total of 12 weeks,
and is often accompanied by the recommendation for bed rest over
several weeks until the inflammation has calmed. Unfortunately,
according to a Cochrane review published in 2003 of 8 randomized
controlled trials, the use of anti-inflammatory treatment in acute
carditis does not appear to improve the risk of developing cardiac
lesions over the long term [32]. Heart failure is mainly treated
supportively, with the use of such medications as digoxin (though
patients are quite sensitive to this medication, with the danger of
potentiating heart block), diuretics, and sodium nitroprusside [21,33].
Surgical options are often considered in correcting the conse-
quences of valvular damage by bouts of rheumatic fever, particularly
when stenosis or regurgitation is severe and unresponsive to medical
treatment alone. In recent years, with the development of new
technology, it has been demonstrated that valve repair is preferable to
valve replacement in the mitral, aortic and tricuspid positions.
Benefits of repair include decreasing the risk of embolic disease,
surgical mortality, and the risk of bleeding associated with warfarin
use necessary for prosthetic valves [26,34].
The arthritis of RF is quite responsive to salicylates and NSAIDs as
well. Treatment of rheumatic chorea generally is supportive, as it
tends to resolve on its own; however, it has been proposed that
steroids may help to shorten the duration of symptoms, and may be
potentially used to treat severe or refractory disease, though this
remains controversial [35]. Other medications that may be of use in
refractory chorea include carbamazepine or valproic acid, though the
risks of toxicity from these medications need to be strongly
considered before treatment initiated [2].
9.1. Antibiotic prophylaxis for rheumatic heart disease
RHD is also a well-known risk factor for infective endocarditis, and
has been estimated to be the cause of valvular damage in 63% of these
cases [1]. Because of this, they were previously categorized alongside
those with prosthetic valves and congenital heart disease, and have
long been recommended to undergo antibiotic prophylaxis prior to
having any dental, gastrointestinal, or genitourinary procedures.
In 2007, however, the AHA released updated guidelines that
significantly differ from previous statements, drastically decreasing
the number of patients requiring infective endocarditis (IE) prophy-
laxis for surgical procedures. These new guidelines are in response to
weighing the risks and benefits of providing antibiotics in these
situations, and to new data that a very small number of cases appear to
be prevented by prophylaxis, believing that IE is much more likely to
stem instead from bacteremia resulting from daily activities. They now
recommend prophylaxis only prior to dental procedures and in the
following individuals: those with a history of IE; those with prosthetic
valves or those with prosthetic material used for cardiac valve repair;
those with congenital heart disease with certain stipulations; and
cardiac transplant recipients with regurgitation secondary to an
abnormal valve. Patients solely with rheumatic heart disease who do
not meet the above criteria now appear to have been removed from
the list of those individuals needing antibiotic prophylaxis [36].
10. Prevention
10.1. Primary prevention
The goal of primary prevention of ARF is to guard against the
development of the initial attack of rheumatic fever by providing
appropriate antibiotics for the initial episode of GAS pharyngitis. Cost
analysis for primary, secondary, and tertiary prevention of RF and RHD
in Pondicherry Union Territory, India found strategies for primary
122 J.L. Lee et al. / Autoimmunity Reviews 9 (2009) 117–123
prevention to be significantly cost effective, with strategies aimed at
diagnosing and treating the initial symptoms of GAS pharyngitis [37].
The ideal treatment is a single intramuscular dose of benzathine
benzylpenicillin, given the ease of compliance; however, a 10 day
course of penicillin V or erythromycin (for those allergic to penicillin)
can also be used [21]. Other measures that are likely to be effective, but
are difficult to implement, include decreasing overcrowding and
improving access to medical care and antibiotics (see Fig. 1).
10.2. Secondary prevention
Those individuals with a history of ARF or RHD have a high risk of
becoming re-infected with GAS, predisposing them to recurrent
rheumatic fever. Secondary prevention is aimed towards preventing
just such an occurrence. According to the most recent WHO Guide-
lines, published in 2004, the antibiotic of choice in secondary
prevention is penicillin [38]. The recommendations are for a continuous
dosing regimen of intramuscular benzathine benzylpenicillin every 3 (in
high risk populations) to 4 weeks. Twice daily oral penicillin V is also an
option but, expectedly, concerns have been raised about long-term
compliance given its dosing frequency. In those who are penicillin
allergic, a daily oral sulfonamide can be used.
It has been recommended that prophylaxis be continued for at
least 5 years after the initial attack, given recurrence rates are the
highest during this period [21]. The American Heart Association's
most recent guidelines, published in 1995, are more explicit in
detailing a longer duration of therapy. In those with residual cardiac
sequelae, prophylaxis is recommended for at least 10 years after the
last episode of RF and until at least 40 years of age. In those without
chronic valvular disease, it is still recommended that they undergo at
least 10 years of therapy or until well into adulthood [39].
In a closer look at the literature published regarding penicillin
dosing for secondary prevention, a recent Cochrane review examined
nine studies that researched the use of penicillin in children and
adults with a history of rheumatic fever. The following conclusions
were gleaned: (1) penicillin was better than placebo in preventing
recurrent attacks; (2) intramuscular penicillin was preferable to oral
penicillin; and (3) more frequent (performed either every 2–3 weeks)
injections of penicillin appeared to be more effective than injections
performed every 4 weeks. However, the authors do emphasize that
Fig. 1. Cornerstones of prevention in rheumatic fever and rheumatic heart disease.
only a small number of studies were available and were of rather poor
quality. As a result, more research likely is necessary to formulate an
optimal dosing guideline.
10.3. Potential for vaccination
Efforts have long been bent towards developing a vaccine as a
method of improving both primary and secondary prevention.
Difficulty, of course, lies in inducing immunity against GAS without
causing the autoimmune reaction that in vitro infection would
normally produce. In addition, given the epidemiology of GAS
infection, protection against different strains may be required,
depending on the endemic region. Particular attention has been
focused on the M protein, which is a virulence factor found on the
surface of GAS. It contains both a C-terminus that is conserved
amongst many streptococcal strains and an N-terminus that has been
found to be important in inducing strain specific immunity. A multi-
valent vaccine that specifically targets the N-terminal antigen in 26
potential serotypes has shown promising results in adults, and may
soon begin clinical trials in children. Other potential targets include
SCPA, MtsA/GRAB, and the cell-wall carbohydrate. The use of IVIG has
been discussed elsewhere [40].
11. Conclusions
Rheumatic fever, particularly because of sequelae from rheumatic
heart disease, still remains a significant cause of morbidity and
mortality in the developing areas of the world. Early and accurate
diagnosis, using the updated Jones' criteria, is key in managing and
preventing severe consequences of this disease. In particular, the
diagnosis of rheumatic carditis may be helped by today's more
sophisticated echocardiographic techniques, though determination of
the extent of pathology of subclinical carditis is still controversial.
Currently, long-term antibiotics are still the mainstay of secondary
prevention, which comes, expectedly, with difficulties in compliance.
The future brings new developments, including research into a
vaccine directed against the various rheumatogenic strains of Strep-
tococcus pyogenes. However, challenges still remain in inducing
immunity against these strains without causing autoimmunity.
 J.L. Lee et al. / Autoimmunity Reviews 9 (2009) 117–123 123

Take-home messages
• Rheumatic fever primarily affects children and adolescents of less
developed nations, particularly those residing in areas of low
socioeconomic status and indigenous areas.
• Rheumatic heart disease remains the most serious sequelae of
rheumatic fever and causes considerable global morbidity and
mortality.
• Rheumatic fever is a result of molecular mimicry following infection
with group A streptococcus (GAS), or Streptococcus pyogenes.
• Diagnosis of rheumatic fever is dependent on the presence of
multiple criteria, including carditis, polyarthritis, Sydenham's
chorea, erythema marginatum, and subcutaneous nodules.
• Accurate diagnosis and compliance to antibiotic prophylaxis are key
to primary and secondary prevention of rheumatic fever.
• Upcoming developments in the development of a vaccine against
group A streptococcus may help to revolutionize the course of future
rheumatic disease.
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High alpha-defensin levels in patients with systemic lupus erythematosus

Innate immunity plays a role in systemic lupus erythematosus (SLE). The objective of this study was to determine the levels of defensins, which
are antimicrobial and immunomodulatory polypeptides, in SLE. Sthoeger ZM. et al. (Immunology 2009; 127: 116-22). Sera from SLE patients
and healthy controls were tested for pro-inflammatory human beta-defensin 2 (hBD-2) and for alpha-defensin human neutrophil peptide 1
(HNP-1).hBD-2 could not be detected by ELISA and its mRNA levels were low in SLE patients and similar to those found in controls. In contrast,
the mean alpha-defensin level in the sera of all SLE patients (11.07 ± 13.92 ng/microl) was significantly higher than that of controls (0.12 ± 0.07
ng/microl). Moreover, 60% of patients, demonstrated very high serum levels (18.5 ± 13.36 ng/microl) and 50% showed elevated gene
expression in polymorphonuclear cells. High alpha-defensin levels correlated with disease activity, but not with neutrophil count. Thus,
activation and degranulation of neutrophils led to alpha-defensin secretion in SLE patients. Given the immunomodulatory role of alpha-
defensin, it is possible that their secretion may activate the adaptive immune system leading to a systemic response.