Chapter 40 ACUTE RHEUMATIC FEVER AND POSTSTREPTOCOCCAL REACTIVE ARTHRITIS Khaled Alsaeid and James T. Cassidy

Acute Rheumatic Fever Definition and Classification Acute rheumatic fever (ARF) is a disease characterized by an inflammatory process that affects several organs of the body. It is one of the few rheumatic diseases for which the cause has been identified—tonsillopharyngitis due to the group A β-hemolytic Streptococcus pyogenes. The streptococcal infection and the onset of the clinical manifestations of ARF are separated by a period of latency of two to three weeks. During this time, the patient is asymptomatic. The clinical presentations include arthritis, carditis, chorea, a characteristic rash, and subcutaneous nodules. Arthritis is the most common but least specific of these manifestations, whereas carditis is the most specific and serious. The pathological process underlying the inflammatory reaction in the various organs is a vasculitis mediated by an immune reaction to the streptococcal infection. This nonpurulent complication of group A streptococcal disease can be prevented by appropriate treatment of the streptococcal pharyngitis.

Epidemiology Incidence and Prevalence ARF was prevalent worldwide until the middle part of the 20th century. The advent of industrialization and improved public hygiene in Western Europe and North America was associated with a sharp decline in the incidence of this disease. During the early part of the 20th century, incidence rates of 100 to 200 cases per 100,000 members of the general population were documented in the United States.1 Although this rate still prevails in developing countries,2 current estimates of the incidence of ARF in children in the United States document a markedly lower incidence rate of 0.5 to 3 cases per 100,000 children.3 Between 1985 and 1990, a marked resurgence of the disease occurred in several areas of the United States.4-13 This dramatic reappearance of what had been an increasingly rare disease was followed by a persistently higher rate in the incidence of ARF in these ­geographical 600

areas.14-16 However, the focal nature of these episodes has not significantly affected the overall prevalence of the disease in the United States.

Age at Onset and Sex Ratio The age-related incidence of ARF follows that of group A streptococcal pharyngitis and peaks between the ages of 6- and 15-years-old. ARF is rarely encountered in the United States in children younger than 5-years-old.17-19 Among adults at high risk for streptococcal pharyngitis, such as military recruits and persons working in crowded settings, the incidence of the disease is higher. There is no difference in the incidence of ARF between males and females.

Geographical and Racial Distribution ARF used to be considered a disease of temperate climates but is now more common in countries with tropical climates, particularly in developing countries. In the United States, the highest seasonal incidence is in the spring, following the peak season of streptococcal pharyngitis in the winter. In other countries, a season of peak frequency is less well defined. Despite the decline of ARF in industrialized countries, its prevalence in developing areas of the world remains very high. Incidence rates per 100,000 population range from 23 in Kuwait, 35 in Iran, to 51 in India. It has been estimated that 95% of the nearly 20 million cases of RHD in the world each year occur in developing countries.20,21 Factors invoked in explaining the decreased incidence of the disease in the United States include less crowding in homes and schools and the increased availability of health care to children.22,23 Observations during the recent resurgence of ARF suggest that these factors may not be important because this disease is now occurring primarily in children from middle- to high-income families with ready access to medical care.4 Differences in the incidence of ARF among racial and ethnic groups have been described. In New Zealand, the disease is more common among the Maori population compared with local non-Maoris of similar socioeconomic status.24 ARF in the United States is more prevalent among African Americans and Hispanics than among

40  —  ACUTE RHEUMATIC FEVER AND POSTSTREPTOCOCCAL REACTIVE ARTHRITIS

whites.3 Although genetic factors can account for these racial and ethnic differences, environmental factors may also be instrumental in explaining these observations.2

Etiology and Pathogenesis ARF is a complication of a group A streptococcal tonsillopharyngitis in a predisposed human host; streptococcal pyoderma does not lead to this nonpurulent complication.25 There is no experimental model for this disease. Specific factors that influence its evolution include the characteristics of the etiological organism, the site of the streptococcal infection, and a genetic predisposition of the host (Fig. 40–1). Less than 2% to 3% of previously healthy persons who acquire streptococcal pharyngitis develop ARF. This complication can be prevented by prompt identification and treatment of the streptococcal infection.

Etiological Agent

β-Hemolytic streptococci have been divided into 20 serogroups (A to H and K to V) by Lancefield26 based on immunochemical differences in their cell-wall polysaccharide. The group A Streptococcus is the most common bacterial pathogen associated with tonsillopharyngitis and is the only member that can initiate ARF. Several cellular components and extracellular products produced by this streptococcus in vivo and in vitro have been identified. The streptococcal bacterium consists of a cytoplasm enclosed in a membrane composed predominantly of lipoproteins. This structure is surrounded by a rigid cell wall made up of three components. The primary component is a peptidoglycan that imparts rigidity to the

PATHOGENESIS OF RHEUMATIC FEVER Group A Streptococcus

Susceptible host

Rheumatogenic strains Serotypes M3, M18 Muscoid colonies

Positive for HLA-DR 4,2,1,3,7 DRB1*16 allele Allotype D8/17

Tissue/organ inflammation

Immune reaction

Joints Heart Brain Vascular Connective tissue

Crossreactive antibody and/or cell-mediated immunity

ACUTE RHEUMATIC FEVER FIGURE 40–1  Interactions between the group A Streptococcus and the human host that lead to acute rheumatic fever. HLA, human leukocyte antigen. (Adapted from Ayoub EM: Acute rheumatic fever. In Emmanouilides GC, Riemenschneider TA, Allen HD et al, editors: Moss and Adams’ heart disease in infants, children, and adolescents, including the fetus and young adult, vol II, ed 5, Baltimore, 1995, Williams & Wilkins.)

601

cell wall. A complex of this component and the cell-wall ­polysaccharide elicits arthritis and a recurrent nodular reaction when injected into the skin of experimental animals.27-29 Integrated into the peptidoglycan is the cell-wall polysaccharide or group-specific carbohydrate whose immunochemical structure determines the serogroup specificity. This polysaccharide has been reported to share antigenic determinants with a glycopeptide present in mitral valve tissue.30 Traversing through and extending outside the cell wall as hairlike fimbriae is the M protein, part of a mosaic that also includes the R and T proteins. The M protein is a coiled protein with an α-helical structure consisting of a free, distal, hypervariable aminoterminus and a proximal carboxylterminus anchored to the cell wall.31 This protein is the type-specific antigen of the group A Streptococcus. About 100 M proteins have been identified by differences in immunochemical composition of the variable aminoterminus. A major biological property of the M protein resides in its capacity to inhibit phagocytosis of the streptococcus, which is neutralized by antibody to its aminoterminal region. Immunity to group A streptococcal infections is therefore type specific, predicated on formation of antibodies to the various M proteins. Additional attributes include the association of certain serotypes with potential pathogenicity and virulence. Data procured during a resurgence of ARF confirmed that serotypes 3 and 18, particularly strains that produced mucoid colonies when cultured on blood agar, were primarily associated with the disease.32,33 These two serotypes and the M1 serotype were also associated with severe, invasive group A streptococcal disease, including the streptococcal toxic shock syndrome.34 Studies have indicated that bacterial strains that have conserved parts of the carboxylterminal portion of the M-protein molecule exposed on their cell surface (class I strains) were associated with ARF, whereas strains that did not have this characteristic (class  II) were not.35 It was reported that phages and phagelike elements were the sources for variation in the genome of an M18 isolate, recovered from a patient with ARF, and an M1 strain.36 The pathogenetic importance of the M proteins is supported by data indicating that several epitopes of the M-protein molecule crossreact antigenically with human myocardium, myosin, and brain tissue, ostensibly leading to tissue inflammation.37,38 M protein also functions as a “superantigen.”39 These findings indicate that this streptococcal molecule can induce an inflammatory response in certain tissues by eliciting “autoimmune” antibodies and tissue inflammation by nonspecific stimulation of cell-mediated immunity as a superantigen. The cellular component of the group A streptococci that has been implicated in the pathogenesis of arthritis is the hyaluronate capsule. Like the M protein, this moiety appears to carry epitopes that elicit antibodies that crossreact with human cartilage and synovial hyaluronate.40 Some studies have documented that components of the M3 and M18 epitopes aggregate type IV collagen, a component of the human basement membrane. This reaction is affected in M3 strains by the production of a collagenbinding factor. M18 strains bind collagen through the hyaluronic acid capsule. Patients with ARF have higher

602

SECTION 5  —  ARTHRITIS RELATED TO INFECTION

levels of anticollagen intravenous (IV) antibodies than controls;41 mice immunized with recombinant M3 protein produce anticollagen antibodies. In addition to the cellular components, extracellular products of the group A streptococci have important biological activities and are of practical value in the diagnosis of group A streptococcal infections and their nonpurulent complications. Most of these products are proteins with enzymatic properties, and they possess specific biological and antigenic activity. The streptococcal pyrogenic exotoxins (SPEs) A, B, C, and F (i.e., the mitogenic factor) and Streptococcus supre antigen (SSA) are of particular interest because they act as super­ antigens that induce proliferation of T lymphocytes in vitro and the synthesis and release of several lymphokines in vivo.37-43 This biological activity reflects the ability of SPEs to bind simultaneously to class II major histocompatibility antigens (HLA) of antigen-presenting cells and to the Vβ region of the T-cell receptor. Production of these exotoxins is associated in vivo with a febrile response, alteration of membrane permeability, and enhancement of susceptibility to endotoxin-induced lethal shock.44 Selective activation of lymphocytes has been ascribed to different SPEs. SPE A activates T cells bearing T-cell receptor β-chain segments Vβ8, Vβ12, and Vβ14, whereas SPE B activates T cells bearing segments Vβ2 and Vβ8.45 SPE B has been identified as a cysteine protease that inhibits phagocytosis and enhances dissemination of the organism in vivo. It also induces apoptosis of phagocytic cells.46 The frequencies of the spe genes and their expression vary among group A streptococci; speA is found in 45% of strains, speB in almost all strains, and speC in 30% of strains. SPE A is expressed by 43% and SPE B by 76% of strains.34,47,48 The frequencies of the speA genes and their products are similar among M1 and M3 serotypes.47 The association of certain serotypes with various clinical manifestations of streptococcal infections, such as toxic shock syndrome, has been ascribed to the capacity of the infecting strain to produce one of the SPEs.34,45,47 However, the ubiquity of the production of these toxins makes confirmation of the specificity of these associations questionable.48

ASO test. The other tests, which are no longer readily available, and the streptozyme test, which was widely used at one time, lacked standardization and ­reproducibility and should not be relied on for evidence of antecedent group A streptococcal infection.50 The pattern of the antibody response to the streptococcal antigens is illustrated in Figure 40–2. Antibodies peak approximately three weeks after the acute infection. Because of the period of latency between the infection and the onset of the clinical manifestations of ARF, serum obtained at the time of clinical presentation should document the necessary evidence for antecedent group A streptococcal infection. However, as outlined in Table 40–2, only about 83% of patients with ARF mount an ASO response. Another streptococcal antibody test, such as anti-DNAse B, can provide evidence for an antecedent streptococcal infection in patients in whom an ASO response has not been diagnostic. Table 40–1

Group A streptococcal antigens and corresponding antibody tests Streptococcal Antigen

Antibody Test

Extracellular Product Streptolysin O Streptokinase Hyaluronidase DNAse B NADase Multiple antigens

ASO Antistreptokinase Antihyaluronidase Anti-DNAse B Anti-NADase Streptozyme

Cellular Component M protein Group-specific polysaccharide

Type-specific antibody Anti-A-carbohydrate

ASO, Antistreptolysin O; DNAse B, deoxyribonuclease B; NADase, ­nicotinamide adenine dinucleotidase. Adapted from Ayoub EM: Streptococcal antibody tests in rheumatic ­fever, Clin Immunol Newsletter 3:107-111, 1982.

600 500

The specific antigenicity of most of the streptococcal extracellular products led to the establishment of antibody tests for these products. These tests are used to confirm evidence of a group A streptococcal infection, primarily in patients with ARF and glomerulonephritis. The first and still most universally used is the antistreptolysin O (ASO) test, which was designed by Todd49 to measure neutralizing antibodies to purified streptolysin O in patients with scarlet fever and ARF. This test proved helpful in providing evidence for antecedent group A streptococcal infection, particularly when throat cultures were negative. Subsequently, tests were developed to assay for antibodies to other streptococcal antigens (Table 40–1). The anti-DNAse B test, which assays for antibodies to the most ubiquitous of four deoxyribonuclease isozymes produced by the group A streptococcus (A, B, C, and D), proved to be as reliable and ­reproducible as the

Antibody titers

Streptococcal Antibody Tests

400 300

Upper limit of normal

200 100 1

7 8 2 3 4 5 6 Interval following acute infection (months)

9

FIGURE 40–2  Pattern of antibody response to the extracellular antigens of the group A Streptococcus after tonsillopharyngeal infection in humans. (From Ayoub EM: Streptococcal antibody tests in rheumatic fever, Clin Immunol Newsletter 3:107-111, 1982.)

40  —  ACUTE RHEUMATIC FEVER AND POSTSTREPTOCOCCAL REACTIVE ARTHRITIS

Tests for antibodies to the cell-wall components of group A streptococci are available but not widely used. Determination of type-specific antibody to the different M proteins is employed in epidemiological studies to determine previous exposure or immunity to specific M serotypes. Testing for antibody to the group-specific carbohydrate is available in some laboratories. Because this antibody tends to persist for prolonged periods in patients with rheumatic valvular disease, it may help to confirm the rheumatic cause of mitral valve disease in a patient without a history of ARF.51-54

Mechanism of Tissue Injury Initial suggestions that tissue injury in ARF was caused by direct invasion by the streptococcus or the effect of its extracellular toxins were subsequently replaced by the theory that an immune mechanism was responsible for the inflammatory response in the affected organs. The potential role of an immunological process as the cause of tissue injury was predicated on the observation that the clinical manifestations of ARF occurred after a period of latency of about three weeks from the inciting group

Table 40–2

Frequency of patients with acute rheumatic fever with elevated titers of antistreptolysin O or antideoxyribonuclease B Group

ASO

AntiDNAse B

ASO and anti-DNAse B

Normal controls Acute rheumatic fever Sydenham chorea (isolated)

19% 83%

19% 82%

30% 92%

67%

40%

80%

ASO, Antistreptolysin O; DNAse B, deoxyribonuclease B. Adapted from Ayoub EM, Wannamaker LW: Evaluation of the streptococcal deoxyribonuclease B and diphosphopyridine nucleotidase ­antibody tests in acute rheumatic fever and acute ­glomerulonephritis, Pediatrics 29:527-538, 1962, and from Ayoub EM, Wannamaker LW: Streptococcal antibody titers in Sydenham’s chorea, Pediatrics 38: 946-956, 1966.

Capsule Hyaluronic acid

603

A streptococcal infection. Evidence for involvement of an immune mechanism in pathogenesis was first advanced by Kaplan and coworkers.55,56 These investigators and others described the presence of common antigenic determinants among the cellular components of the group A streptococci and myocardial tissues. Structures that share crossreactive antigenic determinants included components of the M protein and myocardial sarcolemma,55-60 cell-wall carbohydrate, and valvular glycoprotein,30 streptococcal protoplast membrane, and neuronal tissue of the subthalamic and caudate nuclei,61,62 and the hyaluronate capsule, and articular cartilage.40 Based on these studies, it was concluded that antibodies formed against the streptococcal antigens crossreacted with the corresponding tissues and ostensibly led to inflammation in the heart, joints, and brain (Fig. 40–3).37,38 As attractive as the process of “antigenic mimicry” is in explaining the inflammatory reaction in ARF, there are several flaws in this hypothesis. The most compelling of these arguments is the presence of high levels of crossreactive antibodies in the sera of patients who do not have any manifestations of acute carditis or arthritis. An alternative explanation was provided by subsequent studies that documented a potential role for cell-mediated immunity in inducing tissue damage. These studies confirmed that peripheral blood lymphocytes from patients with acute rheumatic carditis were cytotoxic to human myocardial cells in tissue culture.63 Addition of plasma from the same patients abrogated this cytotoxic effect. The latter observation suggested that the crossreactive antibodies elicited by group A streptococci had a protective rather than a detrimental effect on the host. Based on these arguments, the prevalent hypothesis for explaining tissue injury in this disease is that an immunological mechanism involving the humoral or the cellular immune system may be responsible for tissue inflammation in ARF.

Genetic Background Early postulates regarding the epidemiology of rheumatic fever suggested that persons who acquired this disease had a peculiar susceptibility to it. This ­postulate was based on the observation that 30% to 80% of patients who

Joint

Cell wall M-protein, M, and M-associated protein

Group carbohydrate N-acetyl-glucosamine Rhamnose

Protoplast membrane Protein, lipid, glucose

Myocardium Valvular tissue Myocardial sarcolemma Subthalamic and caudate nuclei

FIGURE 40–3  Group A streptococcal components and corresponding human tissues reported to exhibit immunological crossreactivity. (From Ayoub EM, Schiebler GL: Acute rheumatic fever. In Kelley VC, editor: Practice of pediatrics, vol 8, New York, 1987, Harper & Row.)

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SECTION 5  —  ARTHRITIS RELATED TO INFECTION

had had ARF developed a recurrence of the disease after ­subsequent group A streptococcal pharyngitis, whereas only about 2% of normal persons would develop ARF after such an infection.64 Studies by several investigators documented the familial occurrence of the disease.65-67 Citing their studies, these investigators concluded that susceptibility to ARF is inherited as a single recessive gene. More substantial evidence for a genetic association was provided by Khanna and associates,68 who reported that a B-cell alloantigen, designated D8/17, was present in 99% of patients with ARF but in only 14% of normal controls, data that have been confirmed in subsequent studies.69 Further support for the role of genetic factors in susceptibility was provided by studies on the association of this disease with inheritance of the major HLAs .70-78 The results of these investigations, summarized in Table 40–3, document a significant association of susceptibility with class II HLA antigens. These associations with rheumatic heart disease are more evident and consistent among clinically homogeneous patients.79 Studies have also documented an association with ARF and HLA class II alleles, such as with DRB1*1680 and DRB1*07.81 Early investigators proposed that susceptibility to ARF was related to a state of hyperreactivity to streptococcal antigens. Studies of hyperresponsiveness to a number of streptococcal and nonstreptococcal antigens suggested a hyperimmune response to streptococcal extracellular products, particularly streptolysin O, although subsequent reports did not confirm these findings.82,83 Later studies on the immune response to the group A streptococcal group-specific carbohydrate documented an unusual pattern of hyperimmune response to this antigen in patients with rheumatic valvular disease.51-54,84 This response was associated with inheritance of HLA-DR2 and HLA-DR4 antigens.70 This finding is relevant in view of data that indicate that the immune response to streptococcal cell-wall antigen is under genetic control in experimental animals and humans.85-87

Clinical Manifestations Arthritis, carditis, Sydenham chorea (SC), erythema marginatum, and subcutaneous nodules constitute the major clinical manifestations of ARF (Fig. 40–4). A patient may present with only one, two, or more of these manifestations and with varying degrees of severity of each. Although the severity and frequency of these manifestations vary considerably from patient to patient, their overall frequencies in various populations are similar (Table 40–4). Minor manifestations of ARF include fever, arthralgia, abnormal acute phase reactants, and a prolonged PR interval.

Arthritis Arthritis occurs in about 70% of patients. Although it is the most common of the major manifestations, it is relatively less specific than the other major criteria are because it is encountered in such a large number of other rheumatic diseases. As such, it is the most common cause of a ­misdiagnosis of ARF. Despite its lower specificity, the arthritis of ARF has characteristics that can help in its differentiation from that due to other causes. The arthritis primarily affects large joints, particularly the knees, ankles, wrists, and elbows. Small peripheral joints are only occasionally involved, and axial disease occurs rarely, if ever. The arthritis of ARF is characteristically migratory and additive; it is usually initially a monarthritis but can be polyarticular.88 Symptoms in an affected joint may resolve spontaneously within hours of onset, only to reappear in a different joint. The affected joint manifests the cardinal signs of inflammation with swelling, erythema, warmth, and pain. The latter symptom is the most prominent. It occurs at rest and is accentuated by passive or active movement of the joints. The severity of pain induces guarding of the joints, which may lead to pseudoparalysis.

Table 40–3

Reported associations of histocompatibility antigens-DR antigens and alleles with rheumatic fever HLA-DR Study Ayoub et

Location al70

Florida, USA

No. of Patients

Ethnicity

Antigen/Allele

24 48 33 134 40 120 54 40 107

White African American White Indian Arab African American Indian Brazilian (mulatto) Turkish

DRB1*16

Anastasiou-Nana et al71 Jhinghan et al72 Rajapakse et al73 Maharaj et al74 Taneja et al75 Guilherme et al76 Ozkan et al77

Utah, USA New Delhi, India Riyadh, Saudi Arabia Durban, South Africa New Delhi, India San Paulo, Brazil Istanbul, Turkey

Weidebach et al78

Sao Paulo, Brazil

24

Brazilian (mulatto)

Ahmed et al80

Florida, USA

18

White

DR2 DR4 DR3 DR4 DR1 DQw2 DR7 DR3 DR7 DR16 DRw53 DRB1*16

Percent Positive Controls

Patients

32 23 32 26 12 3 32 26 23 33 34

63 54 52 50 65 13 63 58 49 57 83

4

15

HLA-DR, Histocompatibility antigens DR. Adapted from Ayoub EM: Rheumatic fever. In Rich RR, Fleisher TA, Schwartz BD et al, editors: Clinical Immunology: Principles and Practice, St. Louis, 1996, Mosby-Year Book.

40  —  ACUTE RHEUMATIC FEVER AND POSTSTREPTOCOCCAL REACTIVE ARTHRITIS

605

Polyarthritis

Carditis

Erythema marginatum

Chorea 2

4

6

8 10 12 14 16 18 20 22 Time in weeks

FIGURE 40–4  Major manifestations of acute rheumatic fever. This diagram illustrates the expected occurrence of each manifestation. The relative duration in weeks is indicated on the abscissa. The maximum clinical activity of each finding is represented by the peak of the shaded area. The expected frequency of each clinical manifestation is represented by the relative height of each shaded area. Polyarthritis and carditis usually are manifestations of acute disease. Chorea, although it may be an early manifestation, usually occurs about three months after the inciting episode of pharyngitis. It may be unaccompanied by other manifestations of the disease. Erythema marginatum is present for a longer period during and after the initial acute attack. This manifestation, although it is often associated with severe disease, is relatively uncommon in children.

Table 40–4

Frequency of major manifestations of acute rheumatic fever in patients in U.S. and non-U.S. patients U.S. Patients Manifestation Arthritis Carditis Sydenham chorea Erythema ­marginatum Subcutaneous nodules

Non-U.S. Patients

1958-1962

1962-1980

1985-1989

75% 48% 16% 6% 7%

53% 78% 5% 2% 5%

65% 59% 20% 6% 5%

1960-1980 30-79% 41-93% 1-12% 0-16% 1-9%

Adapted from Ayoub EM: Resurgence of rheumatic fever in the United States: the changing pictures of a preventable disease, Postgrad. Med. 92: 133-142, 1992.

Carditis Cardiac inflammation develops in about 50% of the patients. The high frequency of this manifestation reported from developing countries probably reflects a bias toward hospitalization of patients with severe heart disease. Carditis is the most common cause of morbidity and mortality. As with other manifestations, the severity of the carditis is highly variable.89 In some patients, such as those with SC, signs of carditis may be subtle, and cardiac involvement may be missed unless its diagnosis is pursued vigorously with echocardiographic examination.90 Other patients may present with acute pancarditis and severe, life threatening congestive heart failure. Car­ ditis usually occurs in tandem with other major manifestations, such as arthritis. If it is not present initially, carditis may follow arthritis within one week; the onset of carditis beyond this interval is rare. Inflammation of the heart in ARF usually involves the myocardium and endocardium. Pericarditis is a sign of pancarditis: involvement of all cardiac layers in the inflammatory process. It is an ominous development associated with a high mortality rate. Unlike its ­occurrence in other

rheumatic diseases, isolated pericarditis is rare in patients with ARF. Myocarditis occurs during the initial stage of cardiac involvement; it is recognized clinically by the presence of tachycardia at rest in an afebrile patient and obliteration of the normal respiratory variation in heart rate. Myocarditis may be associated with heart block,91 cardiac dysrhythmias, and a prolonged PR interval on electrocardiography. Endocarditis affects principally valvular tissue and leads to the hallmark lesion of rheumatic carditis, valvular insufficiency. The mitral valve is affected alone or in conjunction with other valves in 94% of patients. Isolated mitral valve disease occurs in 65% to 70% of patients, isolated aortic disease in 6% to 13%, and simultaneous involvement of both valves in 29% to 97% of patients. The pulmonic and tricuspid valves are only occasionally affected. Mitral insufficiency or regurgitation is identified clinically by the presence on auscultation of a high-frequency, smooth, holosystolic, apical murmur. This murmur radiates to the left axilla and is best heard with the patient in

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SECTION 5  —  ARTHRITIS RELATED TO INFECTION

a left lateral decubitus position. A mid- to late-diastolic flow murmur of relative mitral stenosis (i.e., CareyCoombs murmur) may be heard in patients with severe mitral insufficiency. The murmur of aortic insufficiency is a high-frequency, diastolic murmur that starts with the aortic component of the second heart sound. It is best heard with the diaphragm of the stethoscope over the third left intercostal space with the patient in the upright position and leaning forward. The murmur of mild aortic insufficiency is faint and often difficult to hear. Murmurs of severe insufficiency are loud and accompanied by a diastolic thrill. In these patients, an increased pulse pressure due to aortic runoff is associated with bounding peripheral pulses (i.e., Corrigan pulse). Mitral and aortic valve stenoses result from valvular scarring and develop during the chronic stages of the disease. Acute heart failure due to severe myocarditis or valvular insufficiency occurs in about 5% of children with ARF. The clinical manifestations vary greatly and include cough, chest pain, dyspnea, orthopnea, and anorexia. Tachycardia, cardiomegaly, and hepatomegaly with tenderness of the liver are present on physical examination.

Sydenham Chorea Also known as St. Vitus’ dance, this manifestation of inflammatory involvement of the basal ganglia and caudate nucleus of the central nervous system occurs in about 15% of patients. A higher frequency of SC was documented by several centers during the recent resurgence of ARF in the United States.60 The latency period between the inciting streptococcal pharyngitis and the onset of clinical signs of chorea is longer than that of the other major manifestations of the disease, averaging two to four months, and sometimes extending to as long as 12 months. A patient with SC presents with persistent involuntary and purposeless movements of the extremities usually symmetric and with muscular incoordination.92 These movements are jerky and most prominent in the face, trunk, and distal extremities. These symptoms disappear during sleep. On examination, the patient grimaces and fidgets constantly. The protruded tongue darts in and out and resembles a bag of worms (i.e., wormian tongue). Speech is halting and explosive, and a steady tone cannot be maintained for even a short time. Extension of the arms above the head leads to pronation of the hands (i.e., pronator sign); extension of the arms anteriorly results in hyperextension of the fingers (i.e., spoon or dishing sign). When the patient is asked to squeeze the examiner’s fingers, the examiner feels irregular contractions of the hand muscles (i.e., milkmaid’s grip or milking sign). Handwriting, particularly drawing vertical straight lines, is clumsy and irregular because of the loss of fine muscle coordination. The patient has difficulty putting on clothes or buttoning a shirt. Such attempts lead to easy frustration and emotional upsets. Parents and teachers often complain about the child’s clumsiness, inability to concentrate on tasks, or emotional lability. These symptoms usually resolve spontaneously in two to three weeks, but in severe cases they may persist for several months and sometimes for years.

A condition akin to SC, at least in pathophysiology, is Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS). This condition represents a subset of childhood obsessive-compulsive disorders (OCD) and tick disorders (TD) triggered by group A beta-hemolytic streptococcus infections. Physicians have long noted that up to 70% of these patients would present with symptoms indistinguishable from classic OCD. In 1998, the National Institute of Mental Health characterized a group of children with a subset of OCD and TD and termed it PANDAS.91 The clinical characteristics that define the PANDAS group are the presence of an OCD or a TD, prepubertal age at onset, abrupt onset relapsing-remitting symptom course, association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity), and temporal association between symptoms exacerbation and Group A streptococcus (GAS) infection. In a systematic clinical evaluation of 50 children who met the diagnostic criteria for PANDAS, Swedo found that patients with PANDAS typically had a young age at illness onset and an abrupt onset of neuropsychiatric symptoms. Group A beta hemolytic streptococcus infection preceded 45 (31%) of 114 exacerbations of TD or OCD.91 Antibrain and antibasal ganglia antibodies have been documented in children with PANDAS, further supporting this hypothesis.92 Prophylaxis with oral penicillin or azithromycin effectively reduced streptococcal infections and neuropsychiatric exacerbations among children with PANDAS. In contrast to SC where carditis is highly prevalent, 70% in some studies, carditis is not associated with PANDAS.93 In fact, the discovery of a carditis in a child with suspected PANDAS indicate SC, rather than PANDAS, as a diagnosis.

Erythema Marginatum Erythema marginatum is characteristic of rheumatic fever and occurs in about 5% of patients. This rash is nonpruritic and macular with a serpiginous erythematous border (Fig. 40–5). The individual lesions are about 0.4 cm in diameter and are usually located on the trunk and proximal inner aspects of the limbs, particularly where they join the trunk. The rash is rare on the face or other exposed areas. It is accentuated by warmth, such as the application of warm towels or a bath. Erythema marginatum is difficult to detect in patients with dark skin.

Subcutaneous Nodules The subcutaneous nodules of ARF that were most common in patients who developed chronic rheumatic heart disease and were a sign of severe involvement are now rare. They are usually located on the extensor surfaces of the joints, particularly the elbows, knees, ankles, and knuckles, and occasionally on the occiput and spine. The overlying skin is not discolored. Their size varies from 0.5 to 2 cm, and they are freely movable. In many respects, they clinically and histologically resemble benign rheumatoid nodules.

Minor Manifestations of the Disease The minor manifestations of fever, arthralgia, and elevated acute phase reactants are nonspecific and encountered in a number of other rheumatic diseases. The severity and

40  —  ACUTE RHEUMATIC FEVER AND POSTSTREPTOCOCCAL REACTIVE ARTHRITIS

607

FIGURE 40–5  Rash of erythema marginatum in an adolescent boy with acute rheumatic fever occurred with its characteristic serpiginous and erythematous margins.

duration of fever vary; the patient may have a temperature of 38.5°C=101°F to 40°C=104°F during the acute phase of the disease. Arthralgia (i.e., pain without objective changes in the joint) should be differentiated from arthritis. Abnormally elevated acute phase reactants are indicators of tissue inflammation and are present during the acute stage of the disease. A prolonged PR interval on the electrocardiogram is another nonspecific finding. It occurs frequently in ARF but does not alone constitute an adequate criterion for carditis; PR prolongation also does not correlate with the ultimate development of chronic rheumatic heart ­disease.

Pathology The inflammation that occurs in ARF is the result of a diffuse vasculitis. The organs most commonly affected are the joints, heart, brain, and peripheral vascular system. The vasculitis affects the smaller vessels and is characterized by proliferation of endothelial cells. This ­vasculitic process is reflected in the rash of ARF; inflammation of collagen occurs primarily in arthritis, valvulitis, and pericarditis. The synovitis of ARF is typified by a mononuclear cell infiltrate with fibrinoid degeneration. Joint cartilage is usually not involved.93,94 Inflammation of the heart, the most serious complication of the disease, usually involves the myocardium and endocardium. Unlike other rheumatic diseases, such as systemic lupus erythematosus (SLE) or juvenile rheumatoid arthritis (JRA), sole involvement of the pericardium is distinctly uncommon in ARF. Valvular endocarditis is the more common and characteristic inflammatory process and the principal cause of chronic cardiac disease. Acute inflammation leads to valvular insufficiency, and persistence of the inflammation results in scarring and stenosis (Fig. 40–6). The mitral valve is the most commonly involved, and mitral insufficiency is the hallmark of rheumatic carditis. A review of the cardiac pathology by Roberts95 indicated that isolated mitral valve disease was of rheumatic origin in 76% of cases, whereas aortic valve disease was ascribable to ARF in only 13% of cases.

FIGURE 40–6  Chronic rheumatic valvular heart disease. Verrucal endocardial thickening was present along the line of closure of the valve leaflets (arrow).

The simultaneous presence of mitral and aortic disease was related to a rheumatic cause in 97% of cases. Serum cardiac troponin I, a sensitive and specific marker of myocardial injury, is not elevated in cases of ARF with cardiac involvement, indicating that congestive heart failure in ARF is related to valvar insufficiency rather than specific myocardial inflammation.96 The histological changes in acute rheumatic carditis are not specific, and the degree of abnormality does not necessarily correlate with the severity of carditis.93,94 In the early stage, when dilatation of the myocardium is present, histological changes can be minimal. Despite this, cardiac function may be severely impaired and associated with a high rate of mortality. Progression of the inflammation leads to an exudative and proliferative reaction in the myocardium characterized by edematous changes followed by a cellular infiltrate of lymphocytes and plasma cells with few granulocytes. CD4- cells predominate in the lymphocytic infiltrate97 Degenerating collagen fibers are visible throughout the tissue as eosinophilic, granular deposits consisting of a mixture of fibrin, globulin, and other substances. This stage is followed by the formation of the Aschoff body.98,99 This lesion consists of a perivascular infiltrate of large cells with polymorphous nuclei and basophilic cytoplasm arranged in a rosette around an avascular center of fibrinoid. The Aschoff body is pathognomonic of rheumatic carditis and occurs most commonly in patients with subacute or chronic carditis. It may develop in any area of the myocardium but is not present in other tissues. Tissue edema and cellular infiltrates characterize the inflammation of valvular tissue. This inflammatory ­process also involves the chordae tendineae. Verrucae may form at

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the edge of the leaflets, preventing the valves from complete closure. Persistent inflammation for several years results in fibrosis and calcification of the valve that lead to stenosis. The pathophysiology of SC is centered in the basal ganglia.100 Magnetic resonance imaging volumetric studies have indicated focal striatal enlargement and response of the chorea to dopamine antagonists. Histological studies have documented cellular infiltration and neuronal loss in the basal ganglia.101,102 Subcutaneous nodules are characterized by a central area of fibrinoid necrosis surrounded by loosely demarcated zones of scattered mononuclear cells. Edema and vascular islands are present, but palisading of epithelioid cells is not well developed. Interstitial collagen fibers and scar formation occupy the outermost layers without formation of a capsule. The histology is not pathognomonic but resembles that of the Aschoff body. Descriptions of the pathological features of erythema marginatum are scant.

Diagnosis Classification Criteria No specific test is available for the definitive diagnosis of ARF. The diagnosis continues to be based on guidelines of clinical and laboratory criteria initially promulgated by T. Duckett Jones and subsequently revised by several committees of the American Heart Association. The latest modification of the Jones Criteria is outlined in Table 40–5.103 The purpose of these guidelines is to assist in the diagnosis of an initial attack of rheumatic fever and to minimize overdiagnosis. As stated under these guidelines, the presence of two major manifestations or one major plus two minor manifestations provides the basis for the diagnosis of ARF—if supported by evidence of antecedent group A streptococcal infection. The latter is a sine qua non for establishing the diagnosis. A positive throat culture or rapid antigen test can confirm an antecedent group A streptococcal pharyngitis. However, the period of latency between the inciting pharyngitis and the onset of ARF reduces the frequency of positive cultures to less than one third of patients.104 More reliable evidence can be obtained by the use of the streptococcal antibody tests listed in Table 40–1. Because of the latency period, serum obtained at the time of the initial evaluation of the patient coincides with the peak of the antibody response (see Fig. 40–2). An elevated ASO or anti-DNAse B level is expected in about 85% of patients (see Table 40–2). When both tests are performed (considered by many to be a reasonable and conservative approach to diagnostic specificity), more than 90% of patients have an elevated titer for one of these tests. If the result of the ASO test is negative, a DNAse B titer should be performed. A fourfold (two-tube) increase or decrease in titers should be demonstrated over time because normal children in many geographical areas may have elevated titers.105 Results of these antibody tests may be normal for most patients with chronic rheumatic heart disease, and a high proportion of patients with SC may have normal ASO or anti-DNAse B titers (see Table 40–2). ­Neither the ASO nor the other streptococcal ­antibody tests are

Table 40–5

Guidelines for the diagnosis of an initial attack of rheumatic fever (Modified Jones Criteria, 1992) Major Manifestations*

Minor Manifestations*

Carditis Polyarthritis Sydenham chorea Erythema marginatum Subcutaneous nodules

Clinical Fever Arthralgia Laboratory Elevated acute phase reactants: Erythrocyte sedimentation rate C-reactive protein level Prolonged PR interval

Supporting Evidence of Antecedent Group A Streptococcal Infection* Elevated or rising streptococcal antibody titers Positive throat culture or rapid streptococcal antigen tests *The presence of two major manifestations or of one major and two minor manifestations indicates a high probability of acute rheumatic fever if supported by evidence of preceding group A streptococcal infection. Adapted from Dajani AS, Ayoub EM, Bierman FZ et al: Guidelines for the diagnosis of rheumatic fever: Jones Criteria, updated 1992, JAMA 87:302-307, 1992.

diagnostic of ARF; they provide supportive evidence for antecedent streptococcal infection. The three acute phase reactants most commonly used in diagnosis are the peripheral blood leukocyte count, the erythrocyte sedimentation rate (ESR), and the C-reactive protein (CRP) level. The leukocyte count is the most variable and least dependable. It is normal in about one half of the patients with ARF. The ESR is markedly elevated in patients with acute disease but may be normal even with severe congestive failure.106 The CRP level is also elevated in patients with acute disease,107 and unlike the ESR, its concentration is not affected by congestive heart failure. These tests are most useful in following the course of the disease and its response to treatment. Serum cardiac troponin 1 levels, known to be associated with myocardial injury, are not elevated in active rheumatic carditis.89,96,108 The role of echocardiography is controversial to date. According to the modified Jones criteria, echocardiographic abnormalities without concomitant clinical findings are not considered in the diagnosis of rheumatic carditis. In certain regions of the world where populations are at increased risk of rheumatic fever, such as the Maori and Pacific people in New Zealand and the aboriginal Australians, echocardiography has a central role in the diagnosis of rheumatic carditis. Australian criteria and the New Zealand guidelines for rheumatic fever diagnosis suggest that subclinical carditis, namely echocardiographic valvulitis without clinical findings, should be accepted as carditis for the diagnosis of rheumatic fever.109 Other studies useful in diagnosis include chest radiography and electrocardiography. A chest radiograph can detect cardiac enlargement or pericardial fluid. These findings are best confirmed by echocardiographic ­studies, which can also define the presence of

40  —  ACUTE RHEUMATIC FEVER AND POSTSTREPTOCOCCAL REACTIVE ARTHRITIS

myocarditis by assessing myocardial contractility and the nature and extent of valvular lesions. Electrocardiography is most useful in confirming abnormalities in conduction and rhythm during acute myocardial inflammation.

Differential Diagnosis Other rheumatic diseases account for most of the disorders misdiagnosed as ARF. JRA can be confused with ARF without carditis (see Chapters 14 to 17). Characteristics indicating a diagnosis of JRA rather than ARF include an onset of oligoarticular arthritis in a child before the age of 5-years-old; absence of erythema of the joint; a protracted, recurrent course with an incomplete response to nonsteroidal antiinflammatory drug (NSAID) therapy; and particularly the absence of evidence for antecedent group A streptococcal infection. Poststreptococcal reactive arthritis (PSRA) poses some difficulty in differentiation from ARF. Clinical findings that should assist in the diagnosis of this disorder are discussed later in this chapter. Other conditions in which joint involvement is common include SLE, Kawasaki disease, mixed connective tissue disease, other reactive arthritides, and serum sickness.110 Infectious arthritis, particularly gonococcal arthritis, and brucellosis in endemic areas, may present a problem in differential diagnosis. Leukemia and hemoglobinopathy with bone infarcts can be mistaken for ARF. Patients with carditis and pericarditis may develop secondary infections by a variety of bacterial, viral, rickettsial, or mycoplasmal agents. Endocardial involvement occurs in patients with bacterial endocarditis and in patients with SLE and Libman-Sacks endocarditis. A murmur and systolic clicks are present in patients with mitral valve prolapse. Some children with Kawasaki disease develop clinically obvious myocarditis and valvular disease during the early stages of illness. In these patients, the lack of evidence for antecedent group A streptococcal infection allows an initial differentiation from ARF. Differentiation of SC from other neurological disorders requires careful evaluation.111 Imaging studies of the ­central nervous system are usually normal for patients with SC. Other neurological conditions that may be confused with SC include congenital or acquired “habitual” TDs, attention-deficit disorders, and obsessive-compulsive behavior.112 ASO and anti-DNAse B tests should provide evidence for antecedent streptococcal infection in more than 80% of children with SC. Chorea is also a characteristic symptom in children with the antiphospholipid antibody syndrome (see Chapter 23).

Treatment The initial treatment of ARF should address the eradication of streptococci that initiated this complication and the inflammatory process that has affected the various organs. Patients with ARF should be promptly evaluated for cardiac involvement. Subsequent management includes prophylaxis to prevent recurrence of streptococcal infections and treatment of residual cardiac disease when present.

609

Eradication of Streptococci Patients should receive a streptococcal eradicating regimen of antimicrobials even if their throat culture or rapid antigen test is negative (Table 40–6).113 Penicillin is the primary agent of choice administered intramuscularly as a single dose or orally for 10 days. The intramuscular route is preferable in children with cardiac involvement because of its greater dependability and efficacy. Patients allergic to penicillin should receive one of the following: a narrow spectrum cephalosporin, clindamycin, azithromycin, or clarithromycin.

Treatment of Clinical Manifestations CARDITIS

Acute carditis requires immediate attention.114 For mild to moderate carditis, aspirin is administered in a dose of 80 to 100 mg/kg/day in four divided doses. This schedule is maintained for four to eight weeks, depending on clinical response, and then is reduced gradually and discontinued during the next four weeks. Other NSAIDs may be as effective as aspirin,115,116 but have not yet been recommended by the expert committee of the American Heart Association. Glucocorticoid therapy is reserved for patients with severe carditis and congestive heart failure, particularly those with pancarditis, in whom it may be life saving. The use of glucocorticoids, rather than aspirin in patients with heart failure, is also justified to avoid solute overload from aspirin. It should be emphasized that neither form of therapy has been demonstrated to influence the subsequent evolution of valvular disease.117-119 Unlike most rheumatic diseases, the use of IV methylprednisone as a single antiinflammatory agent is inferior to conventional treatment with oral prednisone in the control of severe rheumatic carditis.120-122 Prednisone is given orally in a dose of 2 mg/kg once daily. The duration of daily steroid therapy should rarely exceed two weeks, and the drug should be tapered and withdrawn during the next two to three weeks. One week before termination of therapy, aspirin should be instituted (following the regimen described earlier) to avoid the rebound of symptoms and acute phase reactants that occurs when steroid therapy is abruptly terminated. The ESR and CRP levels are essential in monitoring the response to antiinflammatory therapy. In patients with heart failure and a falsely low ESR, a rise in this reactant may occur with recovery; the CRP level is more reliable in monitoring the response in these patients. Ancillary therapy for cardiac failure includes the judicious use of drugs such as digitalis; inotropic agents such as dobutamine, dopamine, or amrinone; vasodilators (captopril or enalapril); and diuretics. General aspects of initial management include bedrest for patients with acute carditis. This recommendation, overly emphasized in the past, led to prolonged confinement in bed and cardiac neurosis and should be discouraged. Gradual resumption of normal activity should be allowed after the acute carditis subsides. Echocardiographic follow-up is predicated on the type

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Table 40–6

Antibiotic regimens for primary prevention (streptococcal eradication) and secondary prevention of rheumatic fever Antibiotic

Dose

Route

Duration

600,000 U for patients 27 kg 27 kg 500 mg 2 to 3 times daily

Intramuscular

Single dose

Oral

10 days

For individuals allergic to penicillin Narrow-spectrum cephalosporins

Variable

10 days

Clindamycin

20 mg/kg/day 3 times daily

Azithromycin

12 mg/kg once daily

Clarithromycin

15 mg/kg/day twice daily

Oral or Oral or Oral or Oral Intramuscular

Every 4 weeks*

Primary Prevention Benzathine penicillin G Penicillin V

Secondary Prevention Benzathine penicillin G Penicillin V Sulfadiazine For individuals allergic to penicillin and ­sulfadiazine Macrolide or azalide

600,000 U for patients 27kg 250 mg twice daily 0.5 g once daily 27 kg

Variable

10 days 5 days 10 days

Oral Oral

Oral

*May be given every 3 weeks in high-risk situation. Adapted from Gerber MA, Baltimore RS, Eaton CB et al: Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal ­pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on ­Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Transitional Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research, Circulation 119:1541-1551, 2009.

and severity of the initial carditis and its response to therapy.121

Prophylaxis of Rheumatic Heart Disease

ARTHRITIS

Medical management after the acute stage of the disease centers on prevention of recurrences of rheumatic fever and continued treatment of residual heart disease, including prevention of bacterial endocarditis. Antimicrobial prophylaxis against streptococcal pharyngitis has proved highly effective in reducing recurrences of rheumatic fever and in preventing cumulative heart damage. Regimens for streptococcal prophylaxis recommended by the American Heart Association are outlined in Table 40–6. Because recurrences of rheumatic fever are most common during the five years after the initial attack,17,37,93 intramuscular benzathine penicillin prophylaxis is preferable and should be given once monthly in areas of low incidence of rheumatic fever and every three weeks in areas endemic to this disease. Oral prophylaxis is acceptable for patients without cardiac involvement. Although sulfonamides are ineffective in eradicating streptococcal infections, these agents are as effective, if not more effective, than oral penicillin for prophylaxis against recurrent streptococcal infections. The American Heart Association has recently revised recommendations on rheumatic fever prophylaxis. Current protocols are based on the risk of reinfection and the development of streptococcal pharyngitis.122 This risk is highest in school-aged children, in persons ­working

The arthritis characteristically pursues a self-limiting course, rarely lasting more than one week in any one joint. A hallmark of the arthritis in this disease is its exquisite sensitivity to salicylates. A dose of aspirin of 50 to 75 mg/kg/day given in three to four divided doses is usually effective. This therapy continues for no more than two weeks and is thereafter gradually withdrawn. A rapid resolution of the fever and a decline in the ESR usually parallel resolution of the arthritis. A lack of improvement of the arthritis within about five days of salicylate therapy should prompt a reconsideration of the correctness of the diagnosis. No data are available regarding the efficacy of other NSAIDs in the treatment of ARF. Steroids should not be used in patients with isolated arthritis. CHOREA

Mild manifestations of SC require only bedrest and avoidance of physical and emotional stress. Although anticonvulsant drugs may help control severe symptoms, the response to these agents is unpredictable. Phenobarbital, haloperidol, carbamazepine, and valproate have been used with varying success. Antiinflammatory agents are not needed for the treatment of chorea.

40  —  ACUTE RHEUMATIC FEVER AND POSTSTREPTOCOCCAL REACTIVE ARTHRITIS

in crowded conditions, military recruits, and those in close contact with children, such as parents, teachers, and health providers. Therefore, patients with carditis should receive prophylaxis well into adulthood, preferably for life, whereas it may be discontinued at the age of 21-years-old in those with no cardiac involvement (although all such patients should receive prophylaxis for a minimum of five years regardless of age).123 Prophylaxis should be continued after surgical valve repair.

Endocarditis Prophylaxis Supplemental doses of antibiotic should be prescribed for surgical or dental procedures in children with known rheumatic heart disease. Specific recommendations vary, depending on the procedure and age of the patient.

Course of the Disease and Prognosis Major morbidity in rheumatic fever is associated exclusively with the degree of cardiac damage. Severe carditis, which leads to chronic residual valvular disease (see Fig. 40–6), primarily occurs in children in developing countries. The availability of cardiac surgery has alleviated to a considerable extent the crippling effect of this complication. Mortality is rare and occurs predominantly in patients with pancarditis. A better understanding of the relationship of streptococcal infection to the occurrence of initial attacks and recurrences of rheumatic fever has led to the institution of prophylactic regimens that have prevented subsequent attacks of the disease and reduced the cumulative heart damage produced by these exacerbations.124 The study by Tompkins and colleagues125 emphasizes the singular value of prophylaxis by confirming that signs of rheumatic valvular disease resolve in about 80% of patients who receive continuous, long-term prophylaxis. This information is of particular importance in encouraging patients with rheumatic heart disease to adhere to the prescribed regimen of prophylaxis. Rheumatic arthritis is self-limited. A rare form of nonerosive but deforming arthropathy ascribed to rheumatic fever (i.e., Jaccoud arthritis) has been reported in adults but does not occur in children.126 It is more commonly associated with SLE. SC and erythema marginatum are also self-limited with no permanent residua. Patients who escape severe heart disease can be assured of a benign course and a good prognosis.

Poststreptococcal Reactive Arthritis Definition and Classification The occurrence of arthritis after group A streptococcal infection in children who did not fulfill criteria for the diagnosis of ARF was described first by Crea and Mortimer in 1959.127 Subsequently, a number of other studies reported on this entity which was designated poststreptococcal reactive arthritis (PSRA).80,128-135 In contrast to the arthritis of ARF, arthritis observed in these patients was nonmigratory, protracted in course, and responded

611

poorly to aspirin or other NSAIDs. Despite these clinical differences, several investigators have maintained that PSRA is an extension of the spectrum of ARF.129,136 Some studies, however, suggest that this syndrome differs significantly in pathogenesis and clinical characteristics from the arthritis of rheumatic fever.137

Epidemiology Although it is difficult to assess accurately, the incidence of this disease in North-Central Florida is estimated to be one to two cases per 100,000 children at risk per year; 17 of 455 patients with rheumatic diseases encountered over a period of two years had PSRA.80,138 This incidence was twice that for ARF during the same period. The age of the patients varied from 5- to 16-years-old with a mean of 9.7-years-old. A slightly but not significantly higher incidence of the disease occurred in males (56% versus 44%). There was no ethnic preponderance.

Etiology and Pathogenesis Evidence for group A streptococcal infection should be documented in all patients. In contrast to ARF, in which throat cultures or rapid antigen tests are positive in one third of patients, results are positive in about 75% of patients with PSRA. This difference can be ascribed to the shorter latency (less than 10 days) for this disease.130,131,134 Streptococcal pharyngitis is associated with an ASO and an anti-DNAse B response in most patients.80 Skin infection does not elicit an ASO response. The high frequency of elevated ASO titers in patients with PSRA suggests that streptococcal pharyngitis is the primary inciting cause of the disease.139

Genetic Background Studies of the relationship of PSRA with HLA-B27 failed to document a significant association;80 only three of 18 (16.7%) white American patients were positive. This ­frequency contrasts with reactive arthritis in children, in which 93% are HLA-B27 positive.140 Further studies, however, documented a significant association of PSRA with HLA class II alleles. Compared with normal controls and patients with ARF, these patients had a significant increase in the frequency of DRB1*01.80 In ARF, there is an increased frequency of the DRB1*16 allele. These associations with DRB1 alleles suggest a common pathogenetic mechanism for PSRA and ARF.

Clinical Manifestations In addition to a pharyngitis present in 66% of patients,80,138 approximately 30% report the occurrence of low-grade fever, and a similar number describe a nonscarlatinal rash that precedes onset of the arthritis. About one half of the children complain of morning stiffness of varying duration. Most patients present with arthritis involving one or more joints. About 10% complain only of arthralgia. The frequency of joint involvement is illustrated in Fig. 40–7. The arthritis is asymmetric and nonmigratory in

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Hip 6

Table 40–7

PIP 8

Proposed criteria for the diagnosis of poststreptococcal reactive arthritis

Wrist 8 Shoulder 4 Others 4

Knee 18

MCP 5 Ankle 14

FIGURE 40–7  Frequency of joint involvement in patients with poststreptococcal reactive arthritis. Values represent the number of patients with involvement of that joint. MCP, metacarpopharyngeal; PIP, proximal interphalangeal. (From Ahmed S, Ayoub EM, Scornik JC et al: Poststreptococcal reactive arthritis: clinical characteristics and association with HLA-DR alleles, Arthritis Rheum 41: 1096-1102, 1998. Copyright © 1998 John Wiley & Sons, Inc. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

70% to 80% and involves joints of the lower extremities in almost all patients. One half of the patients also have arthritis involving the upper extremities.80 Axial disease occurs in 25%; in our experience, these patients account for any possible association with HLA-B27. Cardiac disease was present in 5.8% of 86 patients described in the literature.80 In almost all cases, valvular disease was only detected, if at all, several months after onset. Most of these patients had not been placed on penicillin prophylaxis. The delay in onset of cardiac abnormalities should be contrasted with the carditis associated with ARF, in which cardiac involvement usually occurs during the acute stage of the disease and in tandem with the arthritis. Some investigators have described patients who presented with “silent carditis,” indicating that this complication was not clinically detectable and required echocardiographic studies for confirmation.131 This suggests that the frequency of carditis in this disease may be higher than that reported to date. Extraarticular manifestations include vasculitis, tenosynovitis, and glomerulonephritis.141 Acquired Brown syndrome, the inability to elevate the affected eye in full adduction resulting from inflammatory tenosynovitis of the superior oblique tendon, has been reported in one child.142

Diagnosis and Differential Diagnosis Proposed criteria for the diagnosis of PSRA are in Table 40–7.138 The differential diagnosis includes most of the same arthritides outlined for ARF. The similarity in cause, and in some of the clinical manifestations of both diseases, poses unresolved difficulty in differentiating these two entities. However, as outlined in Table 40–8, clinical and laboratory differences should permit the separation of this entity from ARF and other reactive arthritides in most children.

A. Characteristics of the arthritis 1. Acute-onset arthritis, symmetrical or asymmetrical, ­usually nonmigratory, can affect any joint 2. Persistent or recurrent 3. Poorly responsive to aspirin or nonsteroidal antiinflammatory drugs B. Evidence of antecedent group A streptococcal infection C. Does not fulfill the modified Jones Criteria for the ­diagnosis of acute rheumatic fever Adapted from Ayoub EM, Ahmed S: Update on complications of Group A streptococcal infections, Curr Probl Pediatr 27:90-101, 1997.

Table 40–8

Clinical and laboratory characteristics of poststreptococcal reactive arthritis and acute rheumatic fever Characteristics

PSRA

ARF

Antecedent group A ­streptococcal infection Onset of arthritis after ­infection Migratory arthritis Axial arthritis Heart involvement Response to ASA Association with HLA-B27 Association with HLA-DRβ alleles

Yes

Yes