Rheumatic fever and post-streptococcal arthritis

Best Practice & Research Clinical Rheumatology Vol. 16, No. 3, pp. 481±494, 2002

doi:10.1053/berh.2002.0255, available online at http://www.idealibrary.com on

10 Rheumatic fever and post-streptococcal arthritis Maria Odete E. HilaÂrio

MD

Associate Professor, Universidade Federal de SaÄo Paulo, Brazil Alameda dos Anapurus, 1370 ap 144, 04087-004 SaÄo Paulo, SP Brazil

Maria Teresa S. L. R. A. Terreri

MD

Assistant Professor, Universidade Federal de SaÄo Paulo, Brazil Rua Loefgreen, 2381 ap 141, 04040-004 SaÄo Paulo, SP Brazil

Rheumatic fever resulting from group A b-haemolytic Streptococcus infection continues to be a prevalent disease and an important cause of morbidity and mortality in developing countries. Molecular mimicry and CD4 T lymphocytes, interleukins and adhesion molecules play a crucial role in the pathogenesis of this disease. Arthritis, followed by carditis and chorea, are the main manifestations of the disease. Evidence of asymptomatic carditis has been increasing; however, abnormality identi®ed by echo-Doppler evaluation is not considered as a criterion for diagnosis of rheumatic carditis. Benzathine penicillin is still the best therapeutic option for the treatment of streptococcal infection and secondary prophylaxis, due to its ecacy and low cost. Key words: rheumatic fever; Streptococcus; carditis; echocardiography; anti-streptolysin; penicillin; post-streptococcal arthritis.

RHEUMATIC FEVER Rheumatic fever (RF) is a late in¯ammatory, non-suppurative complication of an upper respiratory tract infection caused by Lance®eld Group A b-haemolytic Streptococcus.1 This multi-system disease is characterized by involvement of the heart, joints, central nervous system, subcutaneous tissue and skin. Except for the heart, these organs are transiently a€ected. Rheumatic carditis is the most frequent and important acquired cardiovascular disease in children and adolescents, and the main cause of death from cardiac disease among subjects younger than 40 years of age in developing countries.2 Epidemiology Rheumatic fever is a ubiquitous disease, but the incidence and prevalence vary among countries. Certain climatic features, such as cold temperatures and humidity, favour streptococcal infections and, therefore, increasing frequency of RF. In addition, low socioeconomic status, unfavourable environmental conditions, malnutrition, poor 1521±6942/02/$ - see front matter

c 2002 Elsevier Science Ltd. All rights reserved. *

482 M. O. E. HilaÂrio and M. T. S. L. R. A. Terreri

hygiene, promiscuity and diculty in accessing medical care have been associated with increasing incidence and prevalence of RF. Accurate data on the incidence of RF in developing countries are not available. Estimates suggest that there might be 10±20 million new cases per year in these countries, and the number of cases increases each year among disadvantaged populations.3 In families in a low socioeconomic group living in developing countries, the annual incidence of RF is 100 to 206 per 100 000 children, and the prevalence is 2.1 per 1000.4,5 The prevalence of rheumatic carditis worldwide varies from 0.55 to 11 per 1000.6,7 RF is most frequently observed in children and adolescents. It is rare before 5 and after 25 years of age, and the highest incidence is observed in children 5±15 years old. There is a slight predominance of females and a higher frequency of chorea among girls.8 In our series of 256 children and adolescents with RF, the mean age of onset of symptoms was 9 years and 7 months, and 60% of the patients were female. NonCaucasians are slightly more frequently a€ected than Caucasians.9 In epidemics of streptococcal pharyngotonsillitis, 3% of a€ected individuals develop RF, whereas in endemic situations, this decreases to 0.3%.10 High RF morbidity and mortality rates are related to cardiac manifestations of the disease. The cardiac involvement may be fatal in the acute phase of the disease, or may lead to chronic rheumatic valvular heart disease. Valvular heart disease is an expensive health care burden.11 In Brazil, approximately 8000 to 10 000 cardiac surgeries per year are performed in public hospitals for treatment of RF sequelae.4

Aetiology and pathogenesis Although RF has been known for many years to be consequent to a streptococcal infection of the oropharynx, its pathogenesis is not completely understood. Genetic and epidemiological evidence suggests that there is a population at risk, and the nature of the streptococcal antigens plays an important role in determining the natural history of the disease. The ®nding that family members of RF patients have a higher probability of developing disease, independent of environmental factors, has led to the hypothesis of a genetic predisposition.12 However, the mode of inheritance is not yet known. During the 1980s and early 1990s the presence of alloantigens (not associated with the HLA system) had been described on the surface of B-cells. These antigens designated 883 and D8/17 could be detected in 72% and 100% of RF patients, respectively, and in 15% of normal individuals.13,14 The D8/17 marker was also present in higher frequency in individuals with obsessive±compulsive disorders and Sydenham's chorea than in controls.15 Studies of the relationships of RF and HLA markers have yielded inconsistent results. Associations with HLA-DR4 in Caucasians,16 HLA-DR2 in blacks,17 and DR3 in populations from India have been described.18 Studies in Brazilians suggested associations with antigens HLA-DR7 and DR-53.19,20 The hypothesis of the existence of a gene for susceptibility to RF, located within or very close to the HLA complex, has been proposed by Gerbase-DeLima et al.21 It is likely that the de®nitive genetic marker for RF has not yet been found. The most important antigenic structures of the Streptococcus are proteins M, R and T located in the external layer of the bacterial cell wall. Di€erences in protein M determine the di€erent serotypes of group A b-haemolytic streptococci. In addition, protein M has potent antiphagocytic activity resulting from immunoglobulin binding

Rheumatic fever and post-streptococcal arthritis 483

through non-immune mechanism. Serotypes associated with RF include M1, M3, M5, M6, M14, M18, M19, and M24. Patients with acute RF have high levels of antibodies to M protein, and this may act like a superantigen, inducing an exaggerated immune response and autoimmunity.22 It is thought that following apparent convalescence of a non-treated streptococcal pharyngitis, breakdown products of the Streptococcus with molecular similarity to human tissues are recognized by the immune system, initiating an autoimmune response.23 This is the basis of the theory of cross-reactivity of molecular mimicry by which the host would promote self-injury due to the presence of common antigenic sequences in their tissues and those of streptococcus (Table 1)24±26. According to this theory common epitopes alter the immune system's ability to distinguish self from non-self.23 More recently it has been shown that Streptococcus shares antigenic similarities with circulating lymphocytes and certain HLA molecules.27 A study carried out in Brazil revealed the presence of antibodies to ribosomal protein of the central nervous system in patients with Sydenham's chorea which was associated with activity.28 The presence of high levels of immune complexes has been observed in the sera and joints of patients with active RF.29,30 CD4‡ T lymphocytes are increased in acute RF in association with decreased CD8‡ T lymphocytes and increased levels of interleukins (ILs).31 It has been suggested that IL-6, IL-8 and TNF (tumour necrosis factor) have a role in the pathogenesis of RF. Levels of these cytokines are increased in the acute phase of the disease and return to normal in the chronic phase.32,33 CD4‡ T cells from patients with active RF cultured with superantigen of b-haemolytic streptococci, the pyrogenic erythrogenic toxin, exhibited a Th1-type response, with production of IL-12, whereas CD4‡ T cells from patients with chronic carditis induced a Th2-type response, with production of IL-4 and IL-10.22 The presence of CD4‡ and CD8‡ lymphocytes within the whole thickness of the valvular wall, as well as expression of VCAM-1 (vascular cell adhesion molecule) on valvular endothelial wall, may indicate an important role for these elements in the pathogenesis of rheumatic carditis.34 Guilherme et al have evaluated reactivity of T cells to protein M5 epitopes in the heart and peripheral blood in patients with rheumatic carditis. The results revealed that lymphocytes from HLA-DR7 and DR-53 patients with severe rheumatic carditis more frequently recognized M5 peptide residues 81 to 96.35 Badr-Eldin hypothesized that the primary factor in the pathogenesis of RF was alteration in the function of mononuclear phagocytes.36 According to this hypothesis, phagocytic abnormalities permit persistence of circulating immune complexes. Table 1. Cross-reaction between streptococcal antigens and human tissuea. Streptococcal antigen

Streptococcal structure

Human tissue

Hyaluronic acid M protein

Capsule Cell wall

Group A carbohydrate

Protoplast membrane

Synovial tissue and cartilage Tropomyosin/myosin, myocardial sarcolemma, Joint and neuronal tissue, T cell epitopes Myocardial sarcolemma, subthalamic and caudate nuclei Myosin and HLA class II

67 kDa protein a

From references 24, 25 and 26. Group A carbohydrate (Ag) is related to cell wall (Streptococcus) and valve tissue (human tissue). Lipoproteins and polypeptides are related to protoplast membrane and myocardial sarcolemma.

484 M. O. E. HilaÂrio and M. T. S. L. R. A. Terreri

The presence of decreased CD8‡ T cells and increased CD4‡ T cells in addition to increased antibody production and immune complex formation, would create a vicious circle. Pathology Pathological features of rheumatic carditis include Anitschkow's myocytes and Ascho€'s nodules in the myocardium.37 Macrophage localized in Ascho€'s nodules produce TNFa and IL-1.38 In the valves there is in®ltration of CD4‡ and CD8‡ T cells and expression of class II MHC antigens in vascular endothelial cells and valvular ®broblasts.34,39 In addition, neo-vascularization is seen. Even in calci®ed valvular lesions of old individuals, a lymphocytic in®ltrate is present, indicating continued progression of valvular disease.34 Clinical manifestations Symptoms and signs of RF usually occur 1±3 weeks after the onset of the streptococcal infection of the oropharynx that is symptomatic in only 60% of cases. General manifestations, including fever, loss of appetite and malaise, may not be present. Acute RF symptoms span 6 to 14 weeks. Carditis Carditis is characterized by in¯ammation of the pericardium, myocardium and endocardium (pancarditis). It is the most severe clinical manifestation of RF and can lead to valvular heart disease, cardiac failure or even death. Carditis occurs in approximately 40±50% of patients at the ®rst attack.7,40 Pericarditis, occurring in 5±10% of patients, is clinically characterized by chest pain, softening of the heart sounds, and/or a pericardial rub. Rarely, it is associated with cardiac tamponade. Abnormalities on electrocardiograph and chest radiograph can be observed; however, the best way to make the diagnosis is by echocardiography. Pericarditis rarely occurs as an isolated manifestation of rheumatic carditis. When pericarditis occurs as alone, juvenile idiopathic arthritis and viral pericarditis should be ruled out before rheumatic fever is considered. Myocarditis occurs in 10% of patients. It may present with signs and symptoms of cardiac failure, including dyspnoea, cough, orthopnoea, tachycardia, gallop rhythm, cardiac arrhythmias, hepatomegaly, nocturia, acute pulmonary oedema and cardiomegaly. Isolated myocarditis is also rare.41 Endocarditis, the most frequent form of cardiac involvement, can be asymptomatic or present with a cardiac murmur.42,43 Murmurs present during the acute phase do not indicate a permanent valvular defect, and in the majority of cases, they are transient. The most frequently a€ected valves are, in the following order, mitral, aortic, tricuspid and pulmonary. On auscultation, an apical systolic murmur that does not change with position or respiration, but may often radiate to the axilla and/or back, indicates the presence of mitral insuciency. An aortic diastolic murmur, usually soft, indicates aortic insuciency. The presence of mitral stenosis is rare in the paediatric age group, and indicates previous cardiac involvement. Recurrent carditis in patients with previous cardiac disease may lead to more ominous cardiac sequelae and can cause death. Arthritis Arthritis, the most frequent and least speci®c manifestation of RF, is observed in 60±80% of patients.7,40,44 The arthritis, frequently migratory, transient and self-limited, usually

Rheumatic fever and post-streptococcal arthritis 485

involves large joints, including knees, ankles, elbows and wrists. It usually lasts 2 to 3 days in each joint, and 2 to 3 weeks in total, disappearing without sequelae. Pain out of proportion to the in¯ammatory signs, and a satisfactory response to anti-in¯ammatory doses of salicylates, are characteristic. However, atypical presentations can occur, including mono- or oligoarthritis, additive or symmetric arthritis, arthritis with duration of greater than 6 weeks, and poor response to salicylates.45±47 Enthesopathy can be occasionally seen.48,49 Early administration of non-steroidal anti-in¯ammatory agents may thwart the development of migratory arthritis, and may obscure the diagnosis. When arthritis is the only major manifestation, de®nitive diagnosis of RF is dicult due to the low speci®city of this feature.

Sydenham's chorea Sydenham's chorea (SC), usually occurring in 10% of patients with RF, has been observed at a higher frequency in some countries in recent years.50,51 SC presents as a hypotonic and hyperkinetic syndrome, clinically characterized by brief, random, involuntary, nonrhythmic movements, hypotonic muscles, frequent falls, dysarthria, diculties in concentration, deterioration of handwriting and slow speech. Emotional lability with irritability and easy crying, muscle weakness and behavioural changes precede the onset of chorea. The involuntary movements are usually, but not always, bilateral, a€ecting the distal limbs and the face. Movements become prominent with auditory or visual stimuli, and disappear during sleep. Neuropsychiatric abnormalities such as obsessive± compulsive disorders have been associated with SC.52 Mercadante et al showed that patients with SC have a higher frequency of major depression, tics, and hyperactivity with attention de®cit compared with patients with other manifestations of RF, and controls.53 SC is self-limited, does not result in sequelae, usually disappears within 2 to 3 months, and rarely lasts for over a year. Although it may be associated with other RF manifestations, SC is usually an isolated late manifestation. For this reason, abnormalities of acute-phase reactants or evidence of streptococcal infection are seldom observed. In a study of 556 children with rheumatic fever, 105 patients had isolated chorea at the ®rst RF episode.50 Of these, 30 (29%) had recurrences of RF, 23 of which were again isolated chorea, supporting the observation that recurrent episodes mimic the original attack.54±56 There are few studies using magnetic resonance imaging (MRI) of the brain in patients with SC.57 In a prospective study of 19 children and adolescents with SC we performed MRI in the acute phase and after 1-year follow-up. Persistent basal nuclei lesions in three patients correlated with a higher number of recurrences and a longer duration of clinical manifestations.

Cutaneous features Erythema marginatum and subcutaneous nodules are rare and self-limited manifestations, and are associated with severe carditis in some studies.41 They occurred in 5 3% of our patients and were associated with carditis in 50%. Erythema nodosum is rare. Other rare manifestations include arthralgia, abdominal pain, epistaxis, pneumonitis, pleuritis, encephalitis and glomerulonephritis.

486 M. O. E. HilaÂrio and M. T. S. L. R. A. Terreri

Laboratory investigations No single laboratory test can con®rm the diagnosis of RF; however, some tests help to characterize the in¯ammatory process and provide evidence of a preceding streptococcal infection. Documentation of in¯ammation Leukocytosis with neutrophilia and mild to moderate anaemia are found. Haemoglobin levels below 90 g/l are usually associated with severe carditis. Lymphocytosis and severe anaemia suggest a di€erential diagnosis that includes leukaemia and sickle-cell anaemia. Acute-phase reactants are always elevated at the onset of acute RF. The erythrocyte sedimentation rate (ESR) is elevated in the ®rst weeks of the disease, and higher levels are found among patients with cardiac involvement. C-reactive protein (CRP) is elevated at the onset of the acute phase and tends to disappear at the end of the second or third week. Both ESR and CRP are a€ected by anti-in¯ammatory medications. Acid alpha-1-glycoprotein and alpha-2-globulin are elevated in the acute phase of the disease and remain elevated for a prolonged time. Their levels are not in¯uenced by antiin¯ammatory medications and they have been used to monitor RF activity. Detection of streptococcal infection Group A Streptococcus is isolated by culture of throat swab in only 15±20% of patients and this may be due to both the latency period between infection and the onset of RF symptoms and the prior use of antibiotic. Non-invasive carriage of group A Streptococcus contributes to the low sensitivity of throat culture in diagnosing a preceding infection. Rapid antigen detection tests from throat swabs have the same limitations as cultures with speci®city of 95% but lower sensitivity.58 Elevated titres of anti-streptolysin O (ASO) con®rm invasive streptococcal infection, but approximately 20% of patients with RF may not have this antibody. In these cases, determination of anti-hyaluronidase, anti-deoxyribonuclease B (anti-Dnase B) and/or anti-streptokinase antibodies may be essential for the diagnosis of recent infection. However, in most developing countries only the ASO test is available in public hospitals. Therefore, serial determinations of ASO at 15-day intervals are recommended. The Streptozyme test simultaneously detects several antibodies to the Streptococcus; however, it has not been shown to have any advantage over the ASO titre. Chest radiograph and electrocardiograph (ECG) The chest radiograph and ECG may be abnormal in only 30% of patients with carditis.59 The chest radiograph usually shows cardiomegaly only in patients with myocarditis or moderate to severe pericardial e€usion. On ECG, repolarization abnormalities characterized by prolonged PR and QT intervals can be observed. These abnormalities are not unique to RF and could be present in systemic juvenile idiopathic arthritis or systemic lupus erythematosus. A persisting, prolonged PR interval is usually a manifestation of cardiac ®brosis rather than an active process, whereas a persisting prolonged QT interval is a manifestation of severe disease and a less favourable outcome. Low-voltage QRS complexes and abnormalities of the ST interval may be seen with pericarditis.

Rheumatic fever and post-streptococcal arthritis 487

Doppler echocardiography Doppler echocardiography is useful in evaluating cardiac performance, and myocardial function over time, and in diagnosing valvular disease and pericarditis. Colour Doppler permits a more accurate assessment of intracardiac blood ¯ow.43 If Doppler echocardiography is normal, and the clinical diagnosis of RF is likely, it should be repeated in 2 to 3 weeks.60 Echocardiographic ®ndings of valvular lesions in the absence of clinical manifestations of carditis have been well described.42,43,51,61,62 Elevli et al observed silent carditis in 63% of patients with isolated chorea.62 A prospective, blind study in our clinic revealed that ®ve of 14 patients without clinical evidence of carditis had valvular insuciency documented by Echo-Doppler; the abnormalities persisted for at least 6 months, and for one patient there was progression of the valvular lesion within 2 years.42 Figueroa et al also found abnormalities on EchoDoppler in 29% of 35 patients with RF without clinical evidence of carditis who were followed prospectively.61 However, asymptomatic cardiac involvement, detected only by Doppler echocardiography, is insucient as a unique criterion of carditis.41 Diagnosis There is no symptom, clinical sign or laboratory test that is pathognomonic of RF, and therefore the diagnosis is based on a combination of clinical and laboratory ®ndings. De®nitive diagnosis may be dicult because of the variability of clinical manifestations. Fifty years ago Jones established criteria that are still an important guide for the diagnosis of RF.1 Over the last ®ve decades four modi®cations have been made, the last in 1992 (Table 2).41 It is important to emphasize that not all patients with RF ful®l these criteria at onset of disease. In the presence of isolated chorea and indolent carditis a diagnosis of RF can be made without ful®lling other Jones criteria.41 Most diculties in considering the diagnosis of RF occur in patients with arthritis as the sole manifestation of the disease. The arthritis of RF is non-speci®c and may be confused with other reactive arthritides, septic arthritis, connective tissue diseases, sickle-cell disease and haemoglobinopathy C, leukaemia, lymphoma and bone tumours. Approximately 13% of patients with leukaemia present with arthritis as the initial manifestation of the disease.63 Another diagnostic diculty arises because of the high frequency of functional or innocent murmurs in healthy children, which may be dicult to di€erentiate from Table 2. Guidelines for the diagnosis of an initial attack of rheumatic fever (Modi®ed Jones Criteria, 1992). Major manifestations

Minor manifestations

Carditis Polyarthritis Sydenham's chorea Erythema marginatum Subcutaneous nodules

Clinical Fever Arthralgia Laboratory Elevated acute-phase reactants ESR CRP Prolonged PR interval on ECG

Diagnosis of RF is made in the presence of two major manifestations or of one major and two minor manifestations if supported by evidence of preceding infection with group A Streptococcus (Dajani et al., 1992).41

488 M. O. E. HilaÂrio and M. T. S. L. R. A. Terreri

abnormal and require referral to a cardiologist. Congenital heart diseases, congenital myxomatous valve, bacterial endocarditis and mitral valve prolapse should also be considered in the di€erential diagnosis of rheumatic carditis. Cardiac involvement associated with connective tissue diseases that present with arthritis, and viral infections with perimyocarditis, may also cause diagnostic diculty. Although the presence of chorea is highly suggestive of RF, when present in isolation other diseases that need to be excluded include viral encephalitis systemic lupus erythematosus. Polycythaemias benign familiar chorea and antiphospholipid antibody syndrome. Treatment The management of RF consists of elimination of the Streptococcus, treatment of carditis, arthritis and chorea, and secondary prophylaxis against recurrent infection. Streptococcus can be eliminated by a single intramuscular injection of benzathine penicillin G in a dose of 600 000 units for patients 5 25 kg or 1.2 million units for those 4 25 kg. Patients with proven penicillin allergy should take erythromycin (30± 40 mg/kg/day) in four divided doses for 10 days. Oral medications are less e€ective, mainly due to low compliance and potentially because of variable absorption. Clarithromycin (for 10 days) or azithromycin (for 5 days) are more e€ective than oral penicillin in eliminating Streptococcus, although the e€ectiveness in the prevention of rheumatic fever has not yet been established.64 Caution should be taken to avoid indiscriminate use of macrolide antibiotics in order to prevent development of resistance to these drugs;65 they are also more expensive and less available for underprivileged populations. Studies investigating the use of amoxicillin/clavulanate and cephalosporins for 5-day treatments have shown clinical ecacy and successful bacteriological elimination.66±68 Such regimens are not currently approved by the Food and Drug Administration in the United States, and further studies are warranted to expand and con®rm these observations. It is important to emphasize that sulfa drugs are not e€ective in eliminating streptococci. In countries such as Costa Rica, having a high incidence of RF, adequate treatment of streptococcal infections may reduce the incidence of disease.69 Carditis is treated with prednisone in doses of 1 to 2 mg/kg/day, divided into two or three doses in the ®rst week, and given as a single daily dose thereafter. Prednisone should be given for 2 to 3 weeks until clinical and laboratory improvement, and subsequently the dose should be tapered over 8 to 12 weeks. Successive dose reductions should not exceed 20% of the previous dose. This regimen has been shown to prevent rebounds of rheumatic activity, even when acetylsalicylic acid (ASA) has not been added to therapy. Intravenous immunoglobulin has not been found to be e€ective in reducing severity of carditis.70 Diuretics and digitalis glycosides are used for the treatment of heart failure. Rest is important, and it should be individualized according to the type and severity of clinical manifestations in each patient. Arthritis is treated with ASA in doses of 80 to 100 mg/kg/day (maximum of 3 g/day) until there is clinical improvement and in¯ammatory indicators are brought under control. The dose should then be reduced to complete 4 to 8 weeks of treatment. For patients with associated carditis treatment with corticosteroid is sucient. Chorea is treated with haloperidol (initial dose of 1 to 2 mg/day up to a maximum of 4±5 mg/day), valproic acid (30 to 40 mg/kg/day) or if needed, pimozide (1 to 6 mg/day) with gradual reduction over the months following disappearance of symptoms. Special attention should be given to side-e€ects of these medications. There was no di€erence in ecacy of haloperidol or valproic acid in a study of 75 patients with SC, but 17% of the

Rheumatic fever and post-streptococcal arthritis 489

patients treated with haloperidol developed central nervous system side-e€ects.8 Although there are no proven bene®ts of using glucocorticoids to treat SC, prednisone (1 mg/kg/day) may be useful in selected patients with very severe symptoms. Secondary prophylaxis is carried out with benzathine penicillin G, in the same dose used for primary treatment. The recommended interval between doses is 4 weeks; however, for populations at high risk, penicillin should be given every 3 weeks.68 It is recommended that patients who develop rheumatic fever without carditis should receive prophylaxis until 18 years of age, or for a minimum period of 5 years for adolescent patients. Patients who develop mild carditis without sequelae should receive prophylaxis up to 25 years of age. In the case of involvement of both mitral and aortic valves, prophylaxis should be maintained inde®nitely.71,72 In the case of penicillin allergy, it is recommended that sulfadiazine be used daily in doses of 500 mg/day for children who weigh 5 25 kg and 1 g/day in those 4 25 kg. Although the frequency of penicillin allergy has been reported to be low (0.7 to 5.8%), initial injections should be administered in a setting with resources for treating severe allergic reactions.73±75 Using skin tests, reactions to minor penicillin determinants and penicillin G were seen in 1.4% of 6764 patients.74 Patients undergoing surgery or dental procedures should received additional prophylaxis with amoxicillin. Tonsillectomy is not recommended for the treatment of RF. It does not modify the course of the disease, and it does not alter the frequency of the ®rst attack or recurrences. Vaccines using streptococcal antigens are being developed for use in genetically susceptible individuals. Initial vaccines have focused on the observation that bactericidal antibodies directed against protein M can persist for up to 30 years.76 There are numerous limitations to obtaining an ideal vaccine. There are more than 100 serotypes of streptococci that could induce speci®c immunity.77 Production of a single vaccine protecting against all serotypes could lead to high immunogenicity and development of disease.76,78 Recent studies have suggested that many antigenic determinants have common epitopes in various or all of the rheumatogenic serotypes. Use of these epitopes is a possible strategy for vaccine development.76,79 POST-STREPTOCOCCAL REACTIVE ARTHRITIS Some authors consider post-streptococcal reactive arthritis (PSRA) to be distinct from RF; others consider it to be part of the same spectrum of disease. The ®rst description of this entity dates from a study by Crea and Mortimer of 18 patients with `scarlatinal arthritis', a term applied to non-purulent arthritis which occurred 10 days after the beginning of scarlet fever, and was distinguished from RF by the short latency period.80 However, 10 of these patients developed acute RF in a follow-up period of 1 to 20 years. The next report in 1982 described 12 children with prolonged arthritis, symmetric in 83%, not responsive to salicylates, and with evidence of a preceding streptococcal infection, but who did not ful®l other diagnostic criteria for RF81. The authors felt that these patients were more similar to reactive arthritis associated with enteric pathogens than to RF, and suggested that this could be the result of antigenic changes in the Streptococcus. Subsequent reports of PSRA in children and adolescents have di€ering interpretations and de®nitions.48,82±84 Deighton identi®ed three criteria that distinguish PSRA from RF: presentation of the disease up to 10 days after the infection, prolonged arthritis, or arthritis that is recurrent for 2 months, and lack of response to salicylate or other non-steroidal

490 M. O. E. HilaÂrio and M. T. S. L. R. A. Terreri

anti-in¯ammatory drugs.85 Gibbas and Broussard observed persistence of arthritis for up to 2 months in most, and morning sti€ness for 1 to 2 years in eight of 16 children with PSRA.82 In follow-up, however, four patients developed valvulitis. The authors concluded that these patients should be given penicillin prophylaxis. In some studies children with PSRA have monoarthritis, oligoarthritis or symmetric polyarthritis which is non-migratory, generally acute, very painful, and accompanied by weight loss, a sick appearance and irritability, in association with streptococcal infection.82,83 Other peculiar characteristics include the poor response to salicylates, the shorter latency period, the presence of tenosynovitis, and a longer duration of arthritis.48 Thirty to forty percent of the patients have low-grade fever, and erythema nodosum is quite often present.83,84 De Cunto et al described 12 patients with PSRA, one of whom had arthritis for 2 months, tenosynovitis, and poor response to ASA, and who, 18 months after the acute phase, developed carditis.48 The search for a marker to di€erentiate these two entities has been the object of some studies, although the results are divergent. The DRB1*01 allele was more frequent in patients with PSRA than in those with RF and in controls.83 However, these results were not con®rmed in a subsequent study.86 In their evaluation of 144 patients with RF, Hicks and Yim observed the classical arthritis pattern in 50%, but prolonged arthritis (average 10 weeks) and poor response to ASA in 19.5%.46 Of these, four had carditis, four had subcutaneous nodules, and one had erythema marginatum. The authors concluded that the de®nition of RF arthritis should not be restricted to a migratory, ASA-responsive pattern. Patients with RF and atypical arthritis are frequent in Brazil. Of the 93 outpatients with RF in our clinic who ful®lled at least two major criteria (arthritis associated with carditis or chorea), 36% had additive arthritis or oligoarthritis, 7% monoarthritis, 7% did not respond to ASA, and 5% had arthritis lasting longer than 6 weeks. In a recent study of 109 patients with RF, Pileggi and Ferriani observed atypical arthritis in 47% of the episodes; in 28% it persisted for longer than 4 weeks, in 19% it did not respond to ASA therapy, and in 3% it was monoarticular. In 91% of these episodes of atypical arthritis, patients ful®lled more than one major criterion (carditis and/or chorea).47 In countries where the frequency of RF is very low, specialists may feel more comfortable in distinguishing PSRA from RF on clinical grounds. However, in countries where RF is still prevalent, not to prescribe secondary prophylaxis in such patients is to run too high a risk of not treating a patient who may develop permanent cardiac compromise. As highlighted by Duckett Jones,1 and more recently by Denny,87 patients with arthritis and none of the others major manifestations of acute RF are always the most intriguing to diagnose. The lack of uniformity in the diagnosis and treatment of PSRA re¯ects the need of worldwide accepted criteria for the diagnosis of this entity.88

SUMMARY In summary, rheumatic carditis is the main cause of death by cardiac disease in people less than 40 years of age in developing countries. Reactivity of CD4‡ T cells to M protein, increase in interleukins and molecular mimicry play an important role in pathogenesis. Genetic predisposition, although not yet de®ned, is well established.

Rheumatic fever and post-streptococcal arthritis 491

Clinically, carditis is the most severe manifestation of RF. Arthritis is the most frequent, but less speci®c, manifestation and does not always present the usual described characteristics. Chorea is increasing in frequency and is being associated with neuropsychiatric disorders and frequent recurrences. Benzathine penicillin is the ®rst choice for treating streptococcal infection and for secondary prophylaxis. Oral drugs are not recommended due to variable compliance. The production of a vaccine for genetically susceptible subjects has long been studied and may become reality in the near future. Practice points . . . .

atypical arthritis can be observed in rheumatic fever silent carditis, although not frequent, must be recognized adequate treatment of Streptococcus infection prevents rheumatic fever benzathine penicillin is the ®rst choice for treatment of Streptococcus infection and for secondary prophylaxis

Research agenda . there is a need for clear de®nition and treatment guidelines for post-streptococcal reactive arthritis . further studies are needed to evaluate abnormalities identi®ed by echo-Doppler as a criterion for the diagnosis of carditis . a rheumatic fever vaccine for genetically susceptible subjects may become reality in the near future

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