Rheumatic disorders associated with streptococcal infections

BaillieÁre's Clinical Rheumatology Vol. 14, No. 3, pp. 559±578, 2000

doi:10.1053/berh.2000.0093, available online at http://www.idealibrary.com on

8 Rheumatic disorders associated with streptococcal infections Edmund K. Li

BSc, MD, FRCP(Lond), FRCP(Edin), FRCP(C), FACP

Associate Professor Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong

The proteins in the cell wall of Streptococcus have many functions, with some proteins being regarded as a marker of their rheumatological potential. High levels of antibodies directed against some proteins are seen in patients with acute rheumatic fever. The theory of molecular mimicry forms the basis of the relationship between the bacteria and the disease acute rheumatic fever. A distinct entity which does not ful®l Jones' criteria, and which is known as post-streptococcal reactive arthritis following infection with b-haemolytic streptococci, is being encountered more frequently. A pyogenic form of arthritis due to Streptococcus is one of the most common and serious joint infections and requires prompt recognition and treatment. Key words: Streptococcus; acute rheumatic fever; post-streptococcal reactive arthritis; streptococcal septic arthritis; diagnosis; management.

Historically, since the 1920s, group A streptococcal infection was known as the causative factor in acute rheumatic fever (ARF). However, it was not until another 60 years later that post-streptococcal reactive arthritis was clearly described and suggested to be a distinct entity. In this review, the biology of this group of organisms and the role they play in the pathogenesis of the rheumatic disorders are delineated, and rheumatic disorders that are associated with infection with streptococci are described. Streptococci are a group of Gram-positive bacteria which are among the commonest bacterial pathogens in man. They are generally classi®ed according to the patterns of haemolysis produced when cultivated on sheep-blood agar plates. Complete haemolysis of red cells around colonies is seen with b-haemolytic streptococci. This pattern is characteristic of Streptococcus pyogenes. The viridans streptococci exhibit partial haemolysis (a-haemolysis) around colonies, producing a green colour from which their name is derived. Strains of S. pneumoniae are a-haemolytic, as are many other inhabitants of the upper respiratory and gastrointestinal tracts. Some streptococci are non-haemolytic, and they produce a pattern called g-haemolysis, and are referred to as non-haemolytic streptococci. More precise identi®cation of streptococci, based on the antigenic di€erences in their cell wall carbohydrates and the reaction of speci®c group antisera, as originally described by Lance®eld1, allows further subdivision of the b-haemolytic streptococci into several groups. Organisms belonging to Lance®eld groups A, B, C and G are particularly associated with the septic and reactive arthritides.2 1521±6942/00/030559+20 $35.00/00

c 2000 Harcourt Publishers Ltd. *

560 E. K. Li

THE ARTHRITOGENIC PROPERTIES OF STREPTOCOCCI To understand better the disease processes in rheumatic disorders associated with streptococcal infections, it is important to review the morphological structures of the streptococcus and the host's immune response to these structures. It is now clear that there are antigens or common antigenic sequences associated with some of the bacterial cellular components that may cross-react with di€erent antigens in mammalian tissues (antigenic mimicry). These shared epitopes can impair the ability of the immune system to distinguish self and non-self, and this results in certain organs becoming targets for cross-reactions. Cross-reactions between streptococcal antigens and human tissues Each streptococcal cell has an outer capsule covering a three-layered cell wall, which consists of an M protein, a carbohydrate layer and a mucopeptide layer, and beneath this lies the protoplast membrane.3 Composed of N-acetylglucosamine and glucuronic acid, the capsule of group A streptococci is structurally identical to the hyaluronic acid in human synovial ¯uid to which cross-reactions can occur. Although it has been suggested that the presence of a large mucoid capsule may be one of the more important characteristics of certain rheumatogenic strains, there are no data to con®rm the importance of this capsule in human immune responses.4 The hypothesis of `antigenic mimicry' between bacterial and human antigens has concentrated on two interactions. The ®rst involves the molecular similarity between streptococcal M protein and the sarcolemma of the human myocardial cell; the second is the similarity between the group-speci®c carbohydrates of the group A streptococcus and the glycoprotein of heart valves. The M protein, of which there exist more than 80 distinct serological types, is perhaps the most important virulence factor in group A streptococcal infections of humans.5 The M protein is a helical coiledcoil structure that bears a marked structural homology to the cardiac cytoskeletal proteins tropomyosin and myosin and to many non-helical coiled-coil structures such as vimentin, DNA, lamin and keratin.6 Dale and Beachey have shown that part of the M protein can also cross-react with human sarcolemmal tissue.7 However, the evidence implicating these cross-reactions in the pathogenesis of ARF remains scant.8 Antisera raised against M protein or tropomyosin do not give the same pattern of staining as seen with acute rheumatic fever.3 Antibodies to myosin have not only been detected in the sera of ARF patients, they are also present in the sera in those with post-streptococcal reactions other than ARF. Nonetheless, the most signi®cant crossreactions are seen with the streptococcal membrane structure. When the serum from a patient with ARF is layered over a section of cardiac tissue, the immuno¯uorescent staining patterns of sarcolemma observed are identical with those seen with antisera from rabbits that have been immunized with group A streptococci.3 Cross-reactions occur between group A streptococcal carbohydrate moieties and cardiac valvular glycoproteins.9 The shared antigenic determinant is the N-acetylglucosamine of the group A streptococcus and a similar antigen in the valvular glycoprotein material. Sera from patients with ARF were noted to react to heart valve glycoprotein.10 In addition, patients with ARF and valvular disease have higher titres of this antibody than patients without valvular disease, and these antibodies persist long after the initial attack. The persistence of high titres in patients with rheumatic valvular disease may be related to the slow and sustained release of valvular cross-reactive glycoproteins, thus perpetuating the valvular damage. This

Rheumatic disorders associated with streptococcal infections 561

cross-reaction may be important in the pathogenesis of valvular disease in patients with rheumatic fever.3 Apart from the streptococcal structures resulting in cross-reactive antigens that lead to a toxic e€ect on the host tissue, peripheral mononuclear cell populations have increased reactivity to antigens extracted from group A streptococcal strains in rheumatic fever, as compared to antigens extracted from nephritogenic strains.11 The peptidoglycan portion of the streptococcal cell wall, as well as that of the cell wall of all other Gram-positive organisms with a similar peptidoglycan moiety, is able to stimulate the production of in¯ammatory cytokines such as tumour necrosis factor alpha (TNF-a) in normal human monocyte populations.12 Finally, group A streptococci produce exotoxins which act as superantigens, capable of strongly activating a broad range of T lymphocytes, and inducing the proliferation of T lymphocytes in vitro and the synthesis of several lymphokines in vivo. The superantigens bind to the Vb region of the T-cell receptor and to the class II major histocompatibility antigens of antigen-presenting cells; this interaction results in T-cell proliferation and elevated production of cytokines.12 Attempts have been made to identify class I and class II HLA types and oligotypes that may serve as susceptibility markers for ARF. Some HLA types have been reported more frequently in distinct ethnic groups, but the results are heterogeneous. These discrepancies may be explained by ethnic and geographical biases, and this also prompts speculation that these associations might be of class II genes close to, but not identical to, the putative RF susceptibility gene.13 Recently, a monoclonal antibody, D8/17, was created by immunizing mice with B cells from a rheumatic fever patient. The B cell antigen identi®ed by these antibodies was found to be expressed on an increased number of B cells in 100% of rheumatic fever patients, as compared with 10±15% of healthy controls.14,64 The average number of B cells expressing the rheumatic fever (RF) marker is much greater in patients with rheumatic fever (14.6% D8/17 B cells) as compared to those with post-streptococcal nephritis (3% D8/17 B cells) or normal (5±7% D8/17 B cells) controls. In cases in which the diagnosis of rheumatic fever has been in doubt, the presence or absence of D8/17-positive B cells has been helpful in establishing the diagnosis.14

Rheumatic conditions associated with streptococcal infections Rheumatic fever Acute rheumatic fever (ARF) is the best known in¯ammatory disease that occurs as a delayed non-suppurative sequela to a pharyngeal infection with group A streptococci. It involves the joints, heart, brain, skin and subcutaneous tissues. Following the initial onset of pharyngitis, which may last for only a few days, there is a latent period of between 2 and 3 weeks (average of 19 days). An acute febrile illness characterizes the onset of the disease with manifestations consisting of arthritis, carditis, chorea, subcutaneous nodules and erythema marginatum that may occur simultaneously, in rapid succession, or singly. The clinical episodes are self-limiting, but damage to the heart valves may be severe, resulting in permanent scarring that leads to haemodynamic disturbance and cardiac decompensation. The epidemiology and pathogenesis of ARF can be found in many excellent textbooks of medicine, rheumatology or infectious disease and therefore will not be covered here.

562 E. K. Li

Diagnosis. The diagnosis of rheumatic fever is a clinical one, as there is no speci®c laboratory test that can establish a diagnosis. The most recent modi®cation of the Jones criteria was published in 1992 (Table 1).14

Arthritis Typically the large joints such as the knees, ankles, elbows and wrists are a€ected. The smaller joints of the hands and feet are less commonly involved. The hips are also less commonly a€ected and the spine is rarely involved. Typically, a migratory polyarthritis is seen in 75% of cases when several joints are a€ected in quick succession. The term `migratory' is not meant to signify that the swelling necessarily disappears in one joint when it appears in another. Rather, the various locations overlap in time. Each joint remains swollen until the in¯ammation subsides spontaneously over 2 to 3 weeks. The tenderness can be severe and may be out of proportion to the objective ®ndings. In the majority of patients, the entire duration of polyarthritis lasts for only 1 week, but in one-third of patients it continues for another week, and by the end of 4 weeks all joint swelling should subside. As salicylates and other anti-in¯ammatory drugs are so e€ective in causing prompt relief of joint symptoms, therapy should not be instituted until the clinician is certain that `migratory polyarthritis' is present as it is such a useful sign in aiding the diagnosis. Permanent deformities within the joint do not occur. The Jaccoud type of deformity of the metacarpophalangeal joints is a `post-rheumatic' peri-articular ®brosis and not a synovitis.15 Synovial ¯uid analysis generally reveals a sterile, in¯ammatory ¯uid with the presence of immunoglobulin and a decrease in complement components C1q, C3 and C4, indicating their consumption by immune complexes in the joint ¯uid.16

Carditis Carditis occurs early in the disease, usually during the ®rst few weeks of the illness. Isolated mitral involvement is the most frequent presentation, occurring in nearly 60% of patients with carditis. Isolated aortic valve involvement occurs in 10%, while both mitral and aortic valves are involved in 30% of patients. When carditis is mild, it resolves quickly with disappearance of the mitral regurgitant murmur and without sequelae, as is seen in 65±75% of patients. Right-sided heart valve involvement is distinctly uncommon.17 Severe involvement and recurrences will lead to permanent valvular disease and intractable heart failure.

Sydenham's chorea The latent period between the onset of the arthritis and chorea may be extended from weeks to several months. Chorea is never seen simultaneously with arthritis but often coexists with carditis. It occurs in children, but the incidence declines after puberty and it is not seen in adult men, whereas in pregnant women it may occur in a severe form. Chorea usually runs its course in 8 to 15 weeks, but may last from 1 week to more than 2 years. As soon as the diagnosis of chorea is made, patients should be given secondary prophylaxis for prevention of recurrent attacks as intercurrent infection with group A streptococci can reactivate rheumatic chorea.

Clinical ®ndings arthralgia fever Laboratory ®ndings Elevated acute phase reactants erythrocyte sedimentation rate C-reactive protein Prolonged PR interval on electrocardiogram

Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules

Positive throat culture or rapid streptococcal antigen test Elevated or rising streptococcal antibody titre

Supporting evidence of antecedent group A streptococcal infection

aIf supported by evidence of preceding group A streptococcal infection, the presence of two major manifestations or of one major and two minor manifestations indicates a high probability of acute rheumatic fever.

Minor manifestations

Major manifestations

Table 1. Guidelines for the diagnosis of initial attack of rheumatic fever (Jones criteria, updated 1992).a Rheumatic disorders associated with streptococcal infections 563

564 E. K. Li

Subcutaneous nodules and erythema marginatum Both are rare manifestations occurring in less than 10% of patients. The nodules, which only occur in patients with carditis, vary in number and can be easily overlooked. They appear after the ®rst week of illness and generally disappear after a week or two. Erythema marginatum is an evanescent macular eruption, non-pruritic with rounded borders. It occurs in the early phase of the illness and often persists or recurs. Like the subcutaneous nodules, it appears only in association with carditis. Laboratory ®ndings Ideally, a positive throat culture and an increasing antistreptolysin O (ASO) titre will con®rm a recent streptococcal infection. Unfortunately, documentation of an antecedent group A streptococcal infection by positive throat culture is obtained in only one-third of patients without antibiotic pre-treatment, and in those who have been treated with antibiotics the throat swab may be positive in as few as 10% of patients.18 In older children and young adults, the recollection of having a sore throat approaches 70%; in younger children, this rate is less than 20%.19 Therefore, to document a recent group A streptococcal infection sequential serological monitoring using ASO titre is ideally required, preferably combined with anti-DNAse-B titre because of its higher detection rate and speci®city.20 A positive throat culture may be obtained in asymptomatic carriership, while a negative throat culture may be due to previous antibiotic therapy or to infection with other organisms such as b-haemolytic non-group A streptococi, Mycoplasma species, or viruses which can cause rhinopharyngitis.21 Serological tests used to diagnose streptococcal infections are those directed against extracellular products, including ASO (the most widely used test), anti-DNAse-B (the most widely used ancillary test), antihyaluronidase, and useful third assay, anti-NADase (anti-DPNase) and antistreptokinase. Streptozyme is a concentrate of streptococcal antigens to which sensitized sheep cells will agglutinate in the presence of streptococcal antibodies. This test is not recommended for routine use because of reports of signi®cant variability.15 The ASO test is not speci®c. Streptolysin-O or streptolysin O-like antigens are presented not only by streptococci of group A, C, and G, but also by other bacteria including Bacillus, Clostridium tetani, C. perfringes and Listeria monocytogenes.22 Elevated ASO titres are found in 80% of patients with ARF. Following streptococcal sore throat, the antibody response peaks at 4 to 5 weeks, then falls rapidly over the next several months. The sensitivity of serological testing may be further increased to 90% by using two ± and even up to 95% by using three ± serological tests.23 Sequential monitoring is necessary to prove that a recent streptococcal infection has occurred. It should be remembered that group C and G b-haemolytic streptococci are also capable of causing reactive arthritis24±27 and causing a rise in ASO and anti-DNAse-B antibody titres.27 Thus, elevations of streptococcal antibodies support but do not prove the diagnosis of ARF. Also, the titres of antibodies are not a measure of rheumatic disease activity. The duration of illness is dependent on the extent of the major manifestations. Patients with only arthritis involvement will have the shortest disease duration whereas those with chorea will have a prolonged course of disease. Approximately 75±80% of attacks of ARF subside within 6 weeks; 90% are over in 12 weeks; and 5% may persist for 6 months or more.15 Although recurrences of ARF decrease with age and have declined from 20% to 2±4% in recent outbreaks13, they can occur at any time

Rheumatic disorders associated with streptococcal infections 565

and are most common within 2 years of the original attack, hence the importance of secondary prophylaxis, which is discussed below. Prognosis The prognosis is excellent in patients who do not have carditis during the initial attack. The presence of carditis will prolong the rheumatic duration for 6 months or more. All patients with ARF should be treated at the time of diagnosis as if they have a group A streptococcal infection regardless of the presence of pharyngitis or positive throat cultures. Antibiotic treatment with penicillin V (500 mg twice daily), or erythromycin (250 mg four times daily) should be started immediately and maintained for a 10-day course for eradication of streptococcal pharyngitis. An alternative, for those who may have a compliance problem, is intramuscular benzathine penicillin G (600 000 units in children; 1.2 mega-units in adults) which will also serve as the ®rst prophylactic treatment for the prevention of recurrence. In addition, family members and contacts should have throat culture taken and, if positive, they should be treated for streptococcal infection. For the treatment of clinical manifestations of the disease, such as arthritis, salicylates are very e€ective (4±8 g/day in adults; 80 to 100 mg/kg/day in children), with prompt relief of symptoms after the start of therapy. This treatment may be given for 4±6 weeks until all symptoms are resolved and laboratory values normalized so as to prevent a rebound. Corticosteroid is not indicated in the treatment of arthritis in ARF. Conclusive data on the use of non-steroidal anti-in¯ammatory drugs are yet to become available for ARF. In patients with severe carditis, including congestive heart failure, cardiomegaly or heart block, prednisone should be administered orally (40±60 mg/day) for 2±3 weeks, then withdrawn slowly over 3 weeks. As the patient improves, aspirin (60±70 mg/kg) may be added during the tapering of prednisone and continued for a month after discontinuation of steroids to prevent rebound of symptoms. Congestive heart failure should be treated by conventional medical measures. Recent recommendations for patients with carditis suggest at least a 4-week period of rest.33 Prophylaxis Following the initial eradication of streptococcal infection with antibiotics, secondary prophylaxis should be initiated to prevent subsequent development of upper respiratory tract streptococcal infections. At present, there is no consensus on the frequency of administration of antibiotics. The American Heart Association recommends intramuscular injection of benzathine penicillin G (1.2 million units) every 4 weeks28, and recently a 3-weekly regimen was proposed, but this has not been substantiated to be more e€ective.17 In those who are allergic to penicillin, oral erythromycin (250 mg twice daily) can be used. There is no consensus on the duration of antibiotic prophylaxis. Some have advocated a minimum of 5 years after the last attack, as the risk of recurrence is greatest during the ®rst 3 to 5 years, and continuing prophylaxis in patients until they have reached their early 20s. The American Heart Association recommends prophylaxis for 10 years after the last episode of rheumatic fever, or until adulthood.28 For patients with documented evidence of heart disease who are at risk of repetitive exposure, prophylaxis should be continued inde®nitely.13,29 Primary antibiotic prophylaxis should be recommended to all patients with streptococcal pharyngitis. The di€erentiation of viral causes for sore throat and that

566 E. K. Li

from other infective agents causing tonsillopharyngitis is a clinical one. In areas where the incidence of ARF is high, the use of antibiotics is reasonable in doubtful cases.30 A vaccine A logical approach is to produce a vaccine against group A streptococcal infection to prevent the initial disease in the general population as well as recurrent infections. However, aggregating all of the antigenic epitopes of the many di€erent streptococcal serotypes into a single vaccine might yield such unacceptably high immunogenicity so that the vaccine itself could trigger the disease. Recently, a few M serotype proteins have had their epitopes identi®ed and these might represent a suitable target for a vaccine.31 However, the numerous serotypes and di€erent rheumatological strains of group A streptococci present a major challenge in vaccine development. Post-streptococcal reactive arthritis (PSRA) In children Another type of non-purulent arthritis may be seen following streptococcal infections, occurring in both paediatric patients and adults, di€ering from ARF clinically and lacking the required criteria for the diagnosis of ARF.14 It is known as post-streptococcal reactive arthritis (PSRA). The clinical presentation of the arthritis resembles that of the reactive arthritis associated with enteric organisms rather than rheumatic fever, with prolonged arthritic symptoms lasting several weeks to months. Thus, these patients were labelled as having PSRA or post-streptococcal rheumatic syndrome rather than ARF.32 The ®rst reported series was described by Goldsmith and Long in 1982, with 12 children with protracted arthritis and evidence of antecedent group A streptococcal infection.33 Since that publication, there have been many more reported case series of this form of reactive arthritis occurring in children.32,34±44 Clinical features A total of nine case series involving 138 children with PSRA reported in the literature up to 1999 have been reviewed.33±36,40±44 Two other case reports consisting of three patients were not included.32,37 The clinical data and characteristics of childhood PSRA are summarized in Table 2. Onset Between 44 and 63% of patients had a history of sore throat prior to the onset of arthritis.33,36,37,42±44 The interval between pharyngitis and the onset of arthritis varied from 7 to 11 days.43,44 Although a fever greater than 1018F at the onset was common33,37, 61% of patients remained afebrile throughout the course of their illnesses.32,37,40,43,44 Rashes are not common33,37,44, but when present they can be urticarial or maculopapular, associated with intense cutaneous hyperaesthesia33, or a non-speci®c rash that is not typical of Still's disease, or erythema marginatum.37 Arthritis The characteristics of the arthritis are variable and include migratory polyarthritis34,38,40,42, non-migratory33,34,36,44, additive polyarthritis38,42, symmetrical33±37,39,

? ˆ information not available. PSRA ˆ post-streptococcal reactive arthritis.

1

75 (25±150)

0 ? ? 10 2 1 ?

Characteristic of arthritis, number of patients monoarthritis oligoarthritis polyarthritis symmetric asymmetric migratory non-migratory

Clinical course Mean duration of symptoms (days) (range), days carditis, number of patients pericarditis, number of patients

7 12 4

1982 12 ? 8.1 (3.5±11)

Symptoms preceding arthritis sore throat fever rash

Year Number of patients Sex, number of males/number of females Mean age (years) (range), years

33

60 (60±365) 4 7 episodes

? ? 1 ? ? 1 ?

? ? ?

1986 16 12/14 ? (5±15)

34

? (?) 6 4

? ? ? ? ? ? ?

? ? 0

1987 7 4/3 ? (5±15)

35

? ? 1 0

0 0 7 ? ? 12 0

9 5 0

1988 12 5/7 9 (4±17)

36

? (180±365) 2 0

? ? ? ? ? 9 ?

? 6 ?

1992 12 8/4 8.9 (?)

40

? (?) 13 0

? ? ? ? ? ? ?

? ? ?

1995 38 21/17 10.6 (?)

41

Study (reference number)

Table 2. Clinical features in children with PSRA.

? (1±330) 0 0

2 1 1 0 0 1 0

3 ? 0

1995 4 2/2 ? (5±12)

42

? (?) 0 0

7 3 2 ? ? 3 ?

12 7 ?

1995 12 7/5 9.5 (5±14)

43

66 (5±240) 1 0

0 ? ? ? 17 ? 21

11 7 7

1998 25 11/14 9.7 (5±16)

44

Rheumatic disorders associated with streptococcal infections 567

568 E. K. Li

asymmetric33,39,44, oligoarthritis42,43 as well as monoarthritis.42,43 The non-migratory pattern is more common than the migratory pattern, and polyarthritis occurs as commonly as monoarthritis, whereas oligoarthritis was the least common. The joints most commonly involved are the large joints such as knees and ankles, rather than the small joints of the hands and wrists.33,44 Hips35,44 and cervical spine35 can also be a€ected. Less than half of the patients involved had morning sti€ness, while involvement of the axial skeleton was present in six patients (24%).44 This form of arthritis is generally non-destructive and self-limited, but symptoms may last for weeks or months. A number of reports have con®rmed the protracted course of the arthritis which can average from 4 to 12 weeks33,36,38,40±44 to as long as 6 to 12 months.40,44 It is the long duration of the arthritis as well as the poor response to aspirin and other non-steroidal anti-in¯ammatory drugs (NSAID)32±35,37,39,42,44 that distinguishes PSRA from the arthritis associated with ARF. Uncommonly, recurrences of arthritis have also occurred.34,36,42 Carditis In contrast to ARF, subcutaneous nodules, erythema marginatum and chorea are absent in children with PSRA. However, rheumatic carditis, has been described in paediatric patients with PSRA. Out of a total of 141 cases of PSRA in the literature, 28 cases (20%) with carditis have been reported (Table 3). Carditis was de®ned as the presence of (1) valvulitis with a characteristic murmur, or diagnosed by Doppler echocardiography in the absence of audible murmurs (silent carditis), (2) congestive heart failure due to myocarditis, and (3) electrocardiographic abnormalities. Isolated pericarditis32±36,40,44 was not considered as carditis. The prevalence of carditis varies according to di€erent reports (Table 3). The prevalence of valvulitis varied from 4 to 71%, a€ecting mitral and/or aortic valves.34±36,40,41 In a series of 38 children from Hawaii41, 32% of patients with PSRA had valvulitis. The overall incidence of carditis occurring in this group was identical to the incidence of carditis in 230 patients with ARF seen over the same timespan at the same institution. Silent carditis involving the mitral valve, detected by Doppler echocardiography without audible murmurs, has been known to occur during or after Table 3. PSRA and cardiac involvement. Reference

Patient number

33 34

12 16

35

7

36a 40 32 41

12 12 1 38

44

25

aPatient

Cardiac abnormality Number of patients Pericarditis Pericarditis Valvulitis Pericarditis Valvulitis ECG abnormality Valvulitis Valvulitis Valvulitis Valvulitis Myocarditis Valvulitis

1 7 episodes 4 4 5 1 1 2 1 12 1 1

developed ARF within 18 months of the ®rst episode. PSRA ˆ post-streptococcal reactive arthritis. ECG ˆ electrocardiogram.

31

24

22

43

59

28

26

29

37

37

45

46

24

47

47

25

Reference Age (years)

M

M

M

M

?

F

F

F

Sex

B hips

R shoulder

Neck

B1 wrists

L MTP

L wrist

L shoulder

B1 elbows

B1 wrists

R knees

Throat

Throat

Throat

1 week

2 weeks

2 weeks

Yes

Yes

Yes

17.5

?

?

2.9

?

?

?

?

(109/l)

Peripheral WBC

ESR

128

?

55

?

?

100

?

?

(mm/hour)

Group G

?

?

streptococci

b-haemolytic

Group A

?

Culture

streptococci

Group G

?

streptococci

Haemolytic

bacteraemia

Yes

?

No

?

?

Fever

B1 knees

?

3 weeks

4 weeks

?

?

Latency perioda

streptococci

Septicaemia

Throat

Throat

Throat

Throat

Foci

B1 elbows

B1 wrists

SI

B1 tarsalgia

(dactylitis)

R toe

B1 S I

B1 ankles

B1 knees

L knee

R hip

Joints a€ected

Table 4. Clinical features of adults with PSRA.

41000

800 units/ml

ml

1200 units/

ml

4800 units/

?

ml

8330 units/

1/640

4800 units

ASOT

±

±

±

±

?

±

?

±

RF

?

?

?

±

‡

‡

?

±

HLA-B27

AS

AS

AS

AS

?

RS

RS

RS

Clinical course

Table 4 continues on next page.

±

±

±

±

?

±

?

±

ANA

Rheumatic disorders associated with streptococcal infections 569

50

26

M

F

Sex

L shoulder

R SI

b-haemolytic streptococci

Maxillary

sinus

0.4 weeks

Yes

17

112

Group A

Culture

aureus

Staphylococcus

Streptococci,

Group C

septicaemia

streptococci

haemolytic

Group B b-

streptococci

Haemolytic

Septicaemia

ESR (mm/hour)

streptococci

15.7

(109/l)

Peripheral WBC

Dactylitis hands

No

Fever

B1 shoulder

8 weeks

Latency perioda

b-haemolytic

Throat

Foci

B1 PIPs

B1 wrists

Joints a€ected

?

±

3200

?

RF

ASOT

?

‡

ANA

?

?

HLA-B27

AS

AS

Clinical course

between pharyngitis and the onset of arthritis. B1 ˆ bilateral; WBC ˆ white blood cell; AS ˆ asymptomatic; RS ˆ recurrent joint symptoms; MTP ˆ metatarsalphalangeal; PIP ˆ proximal interphalangeal; R ˆ right; L ˆ left; ESR ˆ erythrocyte sedimentation rate; ASOT ˆ antistreptolysin O test; RF ˆ rheumatoid factor; ANA ˆ antinuclear antibody test.

aInterval

63

48

Reference Age (years)

Table 4. Continued.

570 E. K. Li

Rheumatic disorders associated with streptococcal infections 571

resolution of the rheumatic illness.32,44 The long-term risk of rheumatic heart disease following PSRA has not been established. Other manifestations Apart from arthritis, carditis, pericarditis and occasional non-speci®c rashes, other clinical features such as abdominal pain or pleural e€usions have rarely been reported.33 Nephritis was not reported, although some patients had microscopic pyuria and haematuria.34 In adults (see Table 5) There are only a handful of isolated case reports describing adults with PSRA24±26,28,37,45±49 and one of the largest series had only 23 patients.27 In many ways, this disease is distinct from that in children in several aspects: (1) none of the patients had prior ARF, (2) most patients responded well to NSAIDs with full recovery after 1 to 20 weeks, and (3) the incidence of carditis was zero. Are PSRA and ARF two entirely distinct entities, or is PSRA a form fruste of ARF? Prior reports di€erentiate PSRA from ARF based on the clinical manifestations such as arthritis occurring within the initial 10 days following streptococcal infection, the nonmigratory pattern of arthritis, the protracted course of arthritis, as well as poor responsiveness to anti-in¯ammatory therapy.33±37 However, some of those patients initially felt to have PSRA subsequently developed carditis, either as a feature of the initial episode or occurring with the recurrence of the disease that better ful®ls criteria for classic ARF.36,39 Studies in immunogenetics in rheumatic fever have provided some interesting evidence that the two conditions are actually one disease with di€erent clinical manifestations. Using monoclonal antibody D8/17, obtained by immunizing mice with Table 5. The clinical features of the 30 adult patients are summarized. Clinical features Erythema nodosum Erythema marginatum Non-speci®c rash Trismus Orchitis Pericarditis Transient 1st degree heart block Cholestatic hepatitis Monoarthritis Oligoarthritis Polyarthritis Morning sti€ness Dactylitis Sacroiilitis Enthesitis Cryoglobulinaemia

Number of patients (%) 8 5 1 1 1 1 2 4 5 8 15 2 2 3 1 2

(27) (17) (3) (3) (3) (3) (7) (13) (23) (37) (50) (7) (7) (10) (1) (7)

572 E. K. Li

B cells from a rheumatic fever patient, the average number of B cells expressing the rheumatic fever (RF) marker is found to be much greater in patients with rheumatic fever than in those with post-streptococcus nephritis or normal controls. While patients with rheumatic fever had a mean of 34% D8/17 B cells, their siblings without rheumatic fever had a mean of 14.6% D8/17 B cells. Patients with post-streptococcal nephritis had a mean of 3% D8/17 B cells, and a low level of B cells (5±7%) bearing D8/17 marker was seen in normal controls.50 These results suggest the presence of at least one necessary factor for susceptibility to RF, and the expression of the marker on B cells is not solely the result of B cell activation by an unde®ned streptococcal antigen.51 Even more interesting is the ®nding that D8/17 antigen is found to be present in both conditions. The antigen tested positive in 88% with PSRA and 80% with ARF52, further providing immunogenetic evidence in support of the hypothesis that PSRA represents a variant of ARF. Management In children. Children with PSRA can develop carditis which may occur during the initial illness or may occur subsequently with other features which may then ful®l the criteria for classic ARF. Available data32,34±36 would lead one to the conclusion that they should be given prophylaxis. In past reports, it took as long as 20 years after the initial episode for some paediatric patients with PSRA taking no antibiotic prophylaxis to develop carditis or rheumatic heart disease.42 Until such time as long-term studies (including D8/17 testing) are available to determine which clinical subgroups of patients with PSRA will develop carditis, one cannot predict which children are at risk. As such is the case, most experts have advocated prophylactic antibiotic treatment for patients with PSRA.32,34,39,41,42,44,53 The recommendation of the American Heart Association is that patients with PSRA should be carefully observed for several months for the subsequent development of carditis28, especially in view of the fact that silent carditis is known to occur.32,44 The committee recommends that physicians administer secondary prophylaxis to these patients for a period of up to 1 year. If carditis is not observed, prophylaxis can be discontinued. If carditis is detected, the patient should be classi®ed as having had rheumatic fever and should continue to receive secondary prophylaxis.28 Others44 have proposed a regimen for prophylaxis be similar to that in patients with ARF who have arthritis, but no carditis, which consists of antibiotic prophylaxis for 5 years or until age 21 years, whichever is longer, as outlined by the American Heart Association.28 In adults. In adults with PSRA, long-term antibiotic prophylaxis has been recommended in the following patients: those with mitral valve or aortic incompetence, those with a single severe extra-articular symptom, more than one episode of an attack of disabling reactive arthritis or enthesitis, and a ®rst-degree relative with a history of ARF.54 Others have suggested a 2-year period of monthly penicillin prophylaxis (benzylpenicillin 1.2 million units) for every patient with PSRA.55 Streptococcal arthritis Staphylococcus aureus remains the most common bacterium identi®ed in patients with non-gonococcal bacterial arthritis, accounting for 60% of all joint infections, with b-haemolytic streptococci being the second most common pathogen, accounting for 10±30%, and other pathogens such as Gram-negative bacilli, Streptococcus pneumoniae

Rheumatic disorders associated with streptococcal infections 573

and Staphylococcus epidermidis accounting for the rest.56 Of the di€erent serogroups of b-haemolytic streptococci that cause septic arthritis, in selected hospital-based studies of bacteraemia, group A, B and G occurred with nearly equal frequency, while group C and F were very uncommon57 (Tables 6±8). Both sexes are equally a€ected, with patients usually in their 50s and mostly having underlying medical conditions. Among patients with group A streptococcal arthritis, a chronic skin disease, a wound, or an autoimmune disease is seen. The clinical course of patients infected with the di€erent serogroups varied. Di€erentiation between di€erent serogroups is dicult on the basis of clinical features with septic arthritis. In patients with group A streptococci, the infection generally results from skin or soft-tissue involvement and tends to have an acute presentation with 1 to 2 days' symptoms with high fever, and a rapid progression of the disease. About one-half of the patients are critically ill and require to be admitted to the intensive care unit on admission with shock and DIC. Monoarthritis is common, involving the knee, with positive blood culture in 56%57 (Table 6). In patients with group B streptococci, the majority have underlying predisposing disease such as diabetes mellitus or malignancy. The onset is less acute with 5 to 7 days' symptoms, and a high incidence of bacteraemia of 86%. Metastatic septic foci can develop even during treatment with antibiotic58 (Table 7). With streptococcal group G infections, polyarticular involvement was unusual57, with bacteraemia in 35% of patients (Table 8). Table 6. Clinical features of group A streptococcal septic arthritis.57 1. 2. 3. 4. 5. 6.

Monoarthritis in 100% Acute onset with 1±2 days of symptoms and high fever Critically ill with septic shock, requiring ICU in the majority Bacteraemia in 56% Underlying soft-tissue infections present or underlying medical conditions coexist Outcome: surgical intervention, high complication and mortality rate

Table 7. Clinical features of group B streptococcal septic arthritis.60±62 1. 2. 3. 4. 5.

Monoarticular arthritis in most, polyarticular with a central distribution involving AC, SC, LD, MS joints Serious underlying conditions such as diabetes mellitus or carcinoma often coexist, predisposing to infection or making control of infection dicult Bacteraemia in 86% Outcome: variable, from substantial functional morbidity with permanent joint damage to full recovery Recurrences can occur

AC ˆ acromioclavicular; SC ˆ sternoclavicular; LD ˆ lumbar disc; MS ˆ manubriosternal Table 8. Clinical features of group G streptococcal septic arthritis.63 1. 2. 3. 4. 5. 6. 7.

Polyarticular in 30% Male predominance Pre-existing abnormal joints in one-third of cases, such as RA, gout, prosthetic joints Bacteraemia 0±33% Underlying immunode®ciency and neoplasia in some patients Cellulitis and bacterial endocarditis are the most common primary foci Good prognosis with antibiotics, some require removal of joint prostheses

574 E. K. Li

Group C streptococcal septic arthritis is rare, with only 16 case reports found in the literature. Group C streptococci can be divided into four species: S. equi, S. zooepidemicus, S. equisimilis and S. dysgalactiae, on the basis of chemical tests. Apart from S. equi, which is the commonest in humans, the others are primarily animal pathogens. Most patients with group C septic arthritis have polyarticular involvement with bacteraemia occurring in half of the cases, and overwhelming infection involving several organ systems has been reported. Death was far more frequent than would have been expected with streptococcal septic arthritis, as was poor outcome of joint disease among survivors.58 Septic arthritis due to group F streptococci is a serious infection in children occurring either as the result of direct inoculation of organisms into the joint space or haematogenous spread from a contiguous infection. It is rare, and there was only one reported case of a normal 10-month-old boy who presented with acute monoarthritis of the knee and had complete recovery following treatment with antibiotic.59

Management The management of patients with streptococcal septic arthritis follows the principles that apply to all patients with septic arthritis.56 The antibiotic of choice is parenteral penicillin G 10 million units a day. For those who are allergic to penicillin, vancomycin 2 g per day is an alternative, especially in those patients in whom Staphylococcus aureus cannot be excluded. Recently, it has been suggested that clindamycin may be superior to penicillin G in the treatment of serious invasive group A streptococcal infection57 but it should not be used until susceptibility of the isolate has been determined. The optimal duration of therapy has not been determined but the author feels that it should be not less than 3 weeks in those without prosthetic implants and not less than 6 weeks in those with infected prostheses. In patients with group C streptococcal arthritis, because of speci®c features of the bacteriological behaviour of this organism, parenteral penicillin G (25 000 unit/kg/day) may not constitute optimal therapy for this serotype. The MIC of penicillin G for some strains of group C streptococci indicates they are tolerant to penicillin, with values for minimal bactericidal concentration (MBC) that are 32- to 512-fold higher than those for the MIC. For this reason, the routine use of penicillin±aminoglycoside regimens is recommended until in vitro methods of sensitivity and bactericidal tests become available.58 Closed-needle aspiration with serial leukocyte counts in the synovial ¯uids should be performed repeatedly, initially daily or twice daily. In those who have loculated e€usions, persistent positive cultures and high leukocyte counts in the synovial ¯uid, open surgical drainage will be necessary. In a recent report, nearly two-thirds of patients required surgical intervention that included irrigation and debridement, removal of infected prostheses and amputation of limbs. Those who were managed without surgery had overwhelming sepsis with poor prognosis.57 The overall mortality rate was 17%. Patients with group A streptococci had the highest mortality, with 33% as compared with 14 and 0% with group B and G streptococci respectively. This mortality rate is similar to the average mortality rate of 30% in patients with group A streptococcal bacteraemia.57 In instances when prosthetic joints are involved, the management should be shared with the orthopaedic surgeon. Particular problems associated with the management of infected prosthesis and with the prophylaxis are beyond the scope of this chapter.

Rheumatic disorders associated with streptococcal infections 575

SUMMARY Streptococci have been shown to be causes of rheumatic disorders such as ARF, PSRA and septic arthritis. At present, the main approach to primary prevention of ARF is to treat all cases of streptococcal pharyngitis with penicillin while the prospect of a vaccine remains elusive. For children with PSRA, they should be treated as those with ARF and be given antibiotic prophylaxis; in adults with PSRA, prophylaxis for 2 years is indicated. Pyogenic streptococcal arthritis remains an important and serious problem in those with predisposing conditions and requires prompt and appropriate antibiotic treatment.

Practice points . a negative throat culture does not exclude a prior streptococcal infection . serial serological monitoring with two or more tests increases sensitivity . streptococcal antibodies, when present in high titre, support but do not prove the diagnosis of ARF . streptococcal antibody titres are not a measure of rheumatic activity . after acute streptococcal pharyngitis, prolonged symptoms of arthritis and multi-system manifestations that do not ful®l the Jones criteria for the diagnosis of ARF would suggest PSRA . PSRA may develop after infections with group A, B or G streptococci . only group A streptococcal infections may be associated with carditis

Research agenda . there is a need for a vaccine against rheumatic fever

REFERENCES 1. Lance®eld RC. A serologic di€erentiation of human and other groups of hemolytic streptococci. Journal of Experimental Medicine 1933; 57: 571. 2. Wessels MR. Streptococcal infections. In Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL (eds) Harrison's Principle of Internal Medicine, 13th edn, pp 617±623. New York: McGraw-Hill, 1994. * 3. Zabriskie JB. Rheumatic fever: the interplay between host, genetics, and microbe: Lewis A. Conner Memorial Lecture. Circulation 1985; 71: 1077±1086. 4. Stollerman GH. Clinical microbiology of group A streptococcus. In Stollerman GH (ed.) Rheumatic Fever and Streptococcal Infection, pp 21±45. New York: Grune and Stratton, 1975. 5. Fischetti VA. Streptococcal M protein: molecular design and biological behavior. Clinical Microbiology Review 1989; 2: 285±314. 6. Manjula BN & Fischetti VA. Trypomyosin-like seven residue periodicity in three immunologically distinct streptococcal M proteins and its implications for antiphagocytic property of the molecule. Journal of Experimental Medicine 1980; 151: 695.

576 E. K. Li 7. Dale JB & Beachey EH. Protective antigenic determinant of streptococcal M proteins sheared with sarcolemmal membrane protein of human heart. Journal of Experimental Medicine 1982; 156: 1165. 8. Cunningham MW, McCormack JM, Talaber LR et al. Human monoclonal antibodies reactive with antigens of the group A streptococcus and human heart. Journal of Immunology 1988; 141: 2760±2766. 9. Goldstein I, Rebeyrotte P, Parlebas J et al. Isolation from heart valves of glycopeptides that share immunological properties with streptococcus haemolyticus group A polysaccharides. Nature 1968; 219: 866±868. 10. Goldstein I & Caravano R. Determination of anti-group A streptococcal polysaccharide antibodies in human sera by a hemmagglution technique. Proceedings of the Society of Experimental Biological Medicine 1967; 124: 1209±1212. 11. Read SE, Reid HFM, Fischetti VA et al. Serial studies on the cellular immune response to streptococcal antigens in acute and convalescent rheumatic fever patients in Trinidad. Journal of Clinical Immunology 1986; 6: 433±441. 12. Zabriskie JB, Kerwar S & Gibofsky A. The arthritogenic properties of microbial antigens. Rheumatic Disease Clinics of North America 1998; 24: 211±226. 13. Gibofsky A, Kerwar S & Zabriskie JB. Rheumatic fever: the relationship between host, microbe, and genetics. Rheumatic Disease Clinics of North America 1998; 24: 237±259. *14. Guidelines for the diagnosis of rheumatic fever: Jones criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the young, American Heart Association. Circulation 1993; 87: 302±307. *15. Bisno AL. Rheumatic fever. In Kelly WN, Harris ED, Ruddy S & Sledge CB (eds) Textbook of Rheumatology, 5th edn, pp 1225±1240. Philadelphia: W.B. Saunders Company, 1997. 16. Svartman M, Potter EV & Poon-King T. Immunoglobulin components in synovial ¯uids of patients with rheumatic fever. Journal of Clinical Investigation 1975; 56: 111±117. 17. Thatai D & Turi ZG. Current guidelines for the treatment of patients with rheumatic fever. Drugs 1999; 57: 545±555. *18. Jansen TLTA, Janssen M & Van Riel PLCM. Acute rheumatic fever or post-streptococcal reactive arthritis: a clinical problem revisited. British Journal of Rheumatology 1998; 37: 335±340. 19. Veasy LG, Wiedneier SE, Orsmond GS et al. Resurgence of acute rheumatic fever in the intermountain area of the United States. New England Journal of Medicine 1987; 316: 318±325. 20. Tolliver PR & Roe MH. Comparison of two slide tests for detection of group A streptococcal antibodies. American Journal of Clinical Pathology 1979; 72: 218±221. 21. Ross K. The diagnostic value of symptoms and signs in acute tonsillitis in children over the age of 10 and in adults. Scandinavian Journal of Infectious Diseases 1985; 17: 259±267. 22. Bernheimer AW. Hemolysins of streptococci: characterization and e€ects on biological membranes. In Wannamaker LW & Matsen JM (eds) Streptococci and Streptococcal Diseases. Recognition, Understanding, and Management, pp 19±31. New York: Academic Press, 1972. 23. Ayoub EM & Wannamaker LW. Evaluation of streptococcal deoxyribonuclease B and diphosphopyridine nucleotidase antibody tests in acute rheumatic fever and acute glomerulonephritis. Pediatrics 1962; 29: 527±538. 24. Rogerson SJ & Beeching NJ. Reactive arthritis complicating group G streptococcal septicaemia. 1990; 20: 155±158. 25. Young L, Deighton CM, Chuck AJ & Galloway A. Reactive arthritis and group G streptococcal pharyngitis. Annals of the Rheumatic Diseases 1992; 51: 1268. 26. Leitch DN & Holland CD. Reactive arthritis, b-haemolytic Streptococcus and Staphyloccus aureus. British Journal of Rheumatology 1996; 33: 912. *27. Jansen TLTA, Janssen M & De Long AJL. Reactive arthritis associated with group C and group G b-hemolytic streptococci. Journal of Rheumatology 1998; 25: 1126±1130. 28. Dajani A, Taubert K, Ferrieri P et al. and the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. Pediatrics 1995; 96: 758±764. 29. da Silva NA & Pereria BA. Acute rheumatic fever: still a challenge. Rheumatic Disease Clinics of North America 1997; 23: 545±568. 30. Arquedas A & Mohs E. Prevention of rheumatic fever in Costa Rica. Journal of Pediatrics 1992; 121: 569±572. 31. Pruksakorn S, Currie B, Brandt E et al. Towards a vaccine for rheumatic fever: identi®cation of a conserved target epitope on M protein of group A streptococci. Lancet 1994; 344: 639±642. 32. Scha€er FM, Argarwal R, Helm J et al. Poststreptococcal reactive arthritis and silent carditis: a case report and review of the literature. Pediatrics 1994; 93: 837±839.

Rheumatic disorders associated with streptococcal infections 577 33. Goldsmith DP & Long SS. Poststreptococcal disease of childhood ± a changing syndrome [abstract]. Arthritis and Rheumatism 1982; 25 (supplement 4): S18. 34. Gibbas DL & Broussard DA. Poststreptococcal reactive polyarthritis ± rheumatic fever or not? [abstract] Arthritis and Rheumatism 1986; 29 (supplement 4): S92. 35. Emery H, Wagner-Weiner L & Magilavy D. Resurgency of childhood poststreptococcal rheumatic syndromes [abstract]. Arthritis and Rheumatism 1987; 30: S80. *36. De Cunto CL, Giannini EH, Fink CW et al. Prognosis of children with poststreptococcal reactive arthritis. Pediatric Infectious Disease Journal 1988; 7: 683±686. 37. Arnold MH & Tyndall A. Poststreptococcal reactive arthritis. Annals of the Rheumatic Diseases 1989; 48: 686±688. 38. Hicks R & Yim G. Poststreptococcal reactive arthritis (PSRA) ± a manifestation of acute rheumatic fever (ARF). Arthritis and Rheumatism 1990; 33 (supplement 9): S145. 39. Fink CW. The role of the streptococcus in poststreptococcal reactive arthritis and childhood polyarteritis nodosa. Journal of Rheumatology 1991; 18 (supplement 29): 14±20. 40. Zemel LS, Hakonarson H, Diana DJ & Zabriskie JB. Poststreptococcal reactive arthritis (PSRA): a clinical and immunogenetic analysis [abstract]. Journal of Rheumatology 1992; 19 (supplement 33): 120. 41. Kurahara DK, Hicks R, Yim H et al. Post-streptococcal reactive arthritis and the frequency of carditis in children [abstract]. Arthritis and Rheumatism 1995; 38: S286. 42. Moon RY, Greene MG, Rehe GT & Katona IM. Poststreptococcal reactive arthritis in children: a potential predecessor of rheumatic heart disease. Journal of Rheumatology 1995; 22: 529±532. 43. Birdi N, Allen U & D'Astous J. Poststreptococcal reactive arthritis mimicking acute septic arthritis: a hospital-based study. Journal of Pediatric Orthopedics 1995; 15: 661±665. 44. Ahmed S, Ayoub EM, Scornik JC et al. Poststreptococcal reactive arthritis. Arthritis and Rheumatism 1998; 41: 1096±1102. 45. Hubbard WN & Hughes GRV. Streptococci and reactive arthritis [letter]. Annals of the Rheumatic Diseases 1982; 41: 434. 46. Gerster JC, Payot M & Rappoport G. Streptococci and reactive arthritis [letter]. Annals of the Rheumatic Diseases 1982; 41: 646. 47. Powell RJ & Jenkins S. Poststreptococcal reactive arthritis [letter]. Annals of the Rheumatic Diseases 1990; 49: 270±271. *48. Schattner A. Poststreptococcal reactive rheumatic syndrome. Journal of Rheumatology 1996; 23: 1297±1298. 49. Jansen TLTA, Janssen M, De Jong AJL & Jeurissen MEC. Are poststreptoccal reactive arthritis (PSRA) and acute rheumatic fever (ARF) separate sequelae of beta-hemolytic streptococcal (BHS) infection? [abstract] Arthritis and Rheumatism 1996; 39 (supplement): S186. *50. Khanna AK, Buskirk DR, Williams RC Jr et al. Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as de®ned by a monoclonal antibody. Journal of Clinical Investigation 1989; 83: 1710±1716. 51. Zabriskie JB, Lavency D, Williams RC et al. Rheumatic fever associated B-cell alloantigen as identi®ed by monoclonal antibodies. Arthritis and Rheumatism 1985; 28: 1047±1051. 52. Birdi N, Allen U, Hosking M & Zabriskie JB. B cell alloantigen D8/17 testing in children with rheumatic fever and poststreptococcal arthritis [abstract]. Arthritis and Rheumatism 1995; 38: S287. 53. Moon RY & Katona IM. Poststreptococcal reactive arthritis in children [letter]. Journal of Rheumatology 1996; 23: 1114. *54. Deighton C. B-haemolytic Streptococcus and reactive arthritis in adults. Annals of the Rheumatic Diseases 1993; 52: 475±482. *55. Jansen TLTA, Janssen M, De Jong AJL & Jeurissen MEC. Poststreptococcal reactive arthritis: a clinical and serological description, revealing its distinction from acute rheumatic fever. Journal of Internal Medicine 1999; 245: 261±267. 56. Goldenberg DL & Reed JI. Bacterial arthritis. New England Journal of Medicine 1985; 312: 764±771. 57. Schattner A & Vosti KL. Bacterial arthritis due to beta-hemolytic streptococci of serogroups A, B, C, F and G. Medicine 1998; 77: 122±139. 58. Ike RW. Septic arthritis due to group C streptococcus: report and review of the literature. Journal of Rheumatology 1990; 17: 1230±1235. 59. Butler KM & Baker CJ. Group F streptococcus. An unusual cause of arthritis. Clinical Orthopedics 1988; 228: 261±264. 60. Deighton C. b-Haemolytic streptococci and musculoskeletal sepsis in adults. Annals of the Rheumatic Diseases 1993; 52: 483±487. 61. Schattner A & Vosti K. Recurrent group B streptococcal arthritis. Clinical Rheumatology 1998; 17: 387±389.

578 E. K. Li 62. Pischel KD, Weisman MH & Cone RO. Unique features of group B streptococcal arthritis in adults. Archives of Internal Medicine 1985; 145: 97±102. 63. Gaunt PN & Seal DV. Group G streptococcal infection of joints and joint prostheses. Journal of Infection 1986; 13: 115±123.