Acute rheumatic fever and streptococci: the quintessential pathogenic trigger of autoimmunity
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- Chakravarty, S.D., Zabriskie, J.B. & Gibofsky, A. Clin Rheumatol (2014) 33: 893. doi:10.1007/s10067-014-2698-8
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Acute rheumatic fever (ARF) is a non-suppurative complication of pharyngeal infection with group A streptococcus. Signs and symptoms of ARF develop 2 to 3 weeks following pharyngitis and include arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum. In developing areas of the world, ARF and rheumatic heart disease are estimated to affect nearly 20 million people and remain leading causes of cardiovascular death during the first five decades of life. ARF still represents one of the quintessential examples of a pathogenic trigger culminating in autoimmune manifestations. In this review, we will focus on the pathogenesis and etiology of ARF and its complications, along with diagnostic and treatment approaches to both ameliorate and prevent long-term sequelae of this potentially debilitating disease.
KeywordsAutoimmunityGroup A streptococcusInflammationMicrobiomeMolecular mimicryRheumatic heart disease
Acute rheumatic fever (ARF) is a delayed, non-suppurative sequela of a pharyngeal infection with group A streptococcus (GAS). Following the initial pharyngitis, a latent period of 2 to 3 weeks occurs before the first signs or symptoms of ARF appear. Its manifestations may be varied and can include arthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum. Notably, damage to cardiac valves may be chronic and progressive, ultimately resulting in decompensatory heart failure.
In developing areas of the world, ARF and rheumatic heart disease are estimated to affect nearly 20 million people and remain leading causes of cardiovascular death during the first five decades of life . Rheumatic fever can occur at any age, but predominantly so in children 5 to 15 years of age [2–4]. Globally, there are 470,000 new cases of rheumatic fever and 233,000 deaths attributable to rheumatic fever or rheumatic heart disease each year, with most occurring in developing countries and among indigenous groups [5, 1]. The mean incidence of ARF is 19 per 100,000 .
In the USA and other developed countries, the incidence of ARF is much lower, with 2 to 14 cases per 100,000 and likely due to improved hygienic standards and routine use of antibiotics for acute pharyngitis [7, 8]. Many cases that do occur are usually part of localized outbreaks [9–13]. With respect to predisposing factors, in developed countries, ARF is generally preceded by GAS tonsillopharyngitis, but not by GAS skin infections . However, data from developing areas where ARF and rheumatic heart disease are endemic suggest that this association is less clear [15–17]. Among aboriginal communities of Australia, for example, the most common manifestation of GAS infection is pyoderma, with symptomatic GAS tonsillopharyngitis and/or pharyngeal colonization being rare [15, 16]. This could be due to the possibility that recurrent pyoderma due to group A streptococci may afford protection against pharyngeal colonization and infection . Alternatively, group G or group C streptococci with certain GAS antigens or enzymes may be important for the pathogenesis of ARF . Among Australian aboriginals with ARF, group G and group C streptococci have been identified in the throat, but not pyoderma lesions [15, 16].
The pathogenic mechanisms that lead to the development of ARF remain multifactorial. It seems abundantly clear that streptococcal pharyngeal infection is required, and genetic susceptibility may play a salient role. Additionally, molecular mimicry is thought to play an important role in the initiation of tissue injury. Despite the lack of evidence for the direct involvement of GAS in the affected tissues of patients with ARF, significant epidemiologic and immunologic evidence indirectly implicates the pathogen in disease initiation. Outbreaks of rheumatic fever closely follow epidemics of streptococcal pharyngitis or scarlet fever with associated pharyngitis . Adequate treatment of a documented streptococcal pharyngitis markedly reduces the incidence of subsequent rheumatic fever . Appropriate antimicrobial prophylaxis prevents the recurrence of disease in patients who have had ARF [20, 21]. Additionally, most patients with ARF have elevated antibody titers to at least one of three anti-streptococcal antibodies (streptolysin “O,” hyaluronidase, and streptokinase), whether or not preceded by sore throat .
In contrast to the high sensitivity of anti-streptococcal antibodies for documenting streptococcal infection, isolation of GAS from the oropharynx of patients with ARF is extremely rare, even in populations that generally do not have access to microbial antibiotics. The clinical documentation of a preceding pharyngitis also appears to be age-related. One study, for example, found that the recollection of pharyngitis approached 70 % in older children and young adults versus only 20 % in younger children . Thus, a high index of suspicion of ARF is important, particularly in children or young adults presenting with signs of arthritis and/or carditis, even in the absence of a documented episode of pharyngitis.
Streptococcal pharyngitis is the only streptococcal infection that has been associated with ARF. Interestingly, there have been many documented outbreaks of impetigo that can cause glomerulonephritis, but very rarely ARF [23, 24]. A study of patients in Trinidad with ARF or acute glomerulonephritis (AGN) diagnosed during an outbreak of scabies and secondary impetigo found that the streptococcal strains colonizing the skin in patients with impetigo were different from those associated with rheumatic fever . The presence of impetigo was associated with AGN, but not with ARF.
Bacterial genetic factors may play an important role in determining the site of GAS infection. Five chromosome patterns of emm genes, which code for M and M-like surface proteins, have been recognized and labeled A–E. Pharyngeal strains typically have patterns A–C, whereas almost all impetigo strains show D and E patterns . Additionally, another factor affecting localization to the pharynx may be CD44, a hyaluronic acid binding protein that appears to act as a pharyngeal receptor for GAS. After intranasal inoculation, GAS colonize the oropharynx in wild-type mice but not transgenic mice that lack CD44 expression .
A comprehensive explanation for why ARF is only associated with streptococcal pharyngitis remains elusive. GAS fall into two main classes based upon differences in the C repeat regions of the M protein . One class is associated with streptococcal pharyngeal infection, and the other (with some exceptions) belongs to strains commonly associated with impetigo. Thus, the particular strain of streptococcus may be crucial in initiating the disease process. The pharyngeal site of infection, with its large repository of lymphoid tissue, also may be important in the initiation of the abnormal host immune response to those antigens cross-reactive with target organs. Importantly, impetigo strains do colonize the pharynx. However, they do not appear to elicit as strong an immunologic response to the M protein moiety as the pharyngeal strains [28, 29]. This observation may prove to be an important factor, especially in light of the known cross-reaction between various streptococcal structures and mammalian proteins.
Antibodies directed against GAS antigens cross-react with host antigens [30–34]. In addition to humoral immunity, observations suggest a role for cell-mediated immunity as well in mediating molecular mimicry found in ARF. A study of human heart intra-lesional T cell clones found that 63 % of patients reacted with meromyosin . Furthermore, many of these clones cross-reacted with myosin, valve-derived proteins, as well as streptococcal M5 peptides. In particular, streptococcal M protein and N-acetyl-beta-d-glucosamine (NABG, the immunodominant carbohydrate antigen of GAS) share epitopes with myosin [30, 32, 33]. Rodents immunized with recombinant streptococcal M protein type 6 develop both valvulitis and focal cardiac myositis . The potential clinical significance of these observations has been illustrated in a study in which monoclonal antibodies were generated from tonsillar or peripheral blood lymphocytes of patients infected with GAS . Some of these antibodies cross-reacted with myosin and certain other proteins. In addition, anti-myosin antibodies purified from patients with ARF cross-reacted with GAS and M protein. Similar antibodies were present in much lower concentrations in some normal subjects. In another study, a monoclonal antibody isolated from a patient with rheumatic carditis was directed against myosin and NABG . The antibody was cytotoxic for human endothelial cell lines and reacted with human valvular endothelium, but this reactivity was inhibited by myosin, and to a lesser extent, laminin, and NABG. The reactivity with the extracellular matrix protein laminin may explain the reactivity against the valve surface.
Molecular mimicry may also be involved in the development of Sydenham chorea. In an animal model, monoclonal antibodies that caused chorea bound to both NABG and mammalian lysoganglioside . Exposure of cultured human neuronal cells to either monoclonal antibodies or serum from patients with chorea led to induction of calcium/calmodulin protein kinase. In contrast, exposure to serum from patients following streptococcal infection that was not complicated by chorea did not have this effect on neuronal cells.
Host genetic factors
Several studies have reported genetic associations with ARF, with some appearing to be major histocompatibility complex (MHC)-related, while others non-MHC-related. Using alloserum from a multiparous donor, an increased frequency of a B cell alloantigen that was not MHC-related was reported in several genetically distinct and ethnically diverse populations of individuals with ARF . In a separate study, monoclonal antibodies were generated by immunizing mice with B cells from patients with rheumatic fever. One of these antibodies, D8/17, was found to identify a marker expressed on increased numbers (>20 %) of B cells in 100 % of patients with ARF of diverse ethnic origins . Conversely, the percentage of D8/17+ B cells ranged from 4 to 6 % in 90 to 95 % of non-affected normal controls. Thus, this marker might identify a population of rheumatic fever-susceptible individuals. Interestingly, the antigen defined by this monoclonal antibody showed no association with or linkage to any known MHC allele, nor did it appear to be related to B cell activation antigens. In contrast, an increased frequency of MHC class II alleles, HLA-DR4 and DR2, has been noted in Caucasian and black patients with rheumatic heart disease . Other studies have implicated DR1 and DRW6 as susceptibility factors in South African black patients with rheumatic heart disease, and a close association with HLA-DR7 and DW53 has been noted in ARF patients in Brazil [41, 42].
These apparently disparate findings suggest that susceptibility to ARF is polygenic. Consequently, the D8/17 antigen might be associated with only one of the genes conferring susceptibility, whereas another might be the MHC encoding for DR antigens. Although the exact explanation remains to be determined, the presence of an increased percentage of D8/17+ B cells appears to identify a population at special risk of contracting ARF.
Major and minor clinical manifestations of ARF (adapted from reference )
Five major manifestations:
Migratory arthritis (predominantly involving the large joints)
Carditis and valvulitis (e.g., pancarditis)
Central nervous system involvement (e.g., Sydenham chorea)
Four minor manifestations:
Elevated acute-phase reactants (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP])
Prolonged PR interval
The natural history of arthritis due to rheumatic fever consists of inflammation affecting several joints in quick succession, each lasting for a few days to a week . The knees, ankles, elbows, and wrists are affected most commonly, with the former typically involved first. The onset of arthritis in different joints usually overlaps, giving a characteristic migratory pattern and thereby providing the classic description of polyarthritis of rheumatic fever. Onset and resolution of arthritis may be rapid (within 1 to 2 days), and the arthritis may be severe enough to restrict movement. Joint involvement is more common and more severe in teenagers and young adults than in children . Though arthritis usually is the earliest symptomatic manifestation of ARF, asymptomatic carditis may develop first. Joint pain usually is more prominent than objective signs of inflammation and is almost always transient. Radiographs of an affected joint may demonstrate a slight effusion but are usually unremarkable. Analysis of the synovial fluid in rheumatic fever with arthritis generally demonstrates sterile inflammatory fluid.
Carditis and Sydenham chorea
Rheumatic fever may cause pancarditis, affecting the pericardium, epicardium, myocardium, and endocardium. The presence of valvulitis is established by auscultatory findings together with echocardiographic evidence of mitral or aortic regurgitation. However, echocardiography findings may be non-specific. Sydenham chorea (also known as chorea minor or “St. Vitus dance”) is a neurologic disorder consisting of abrupt, non-rhythmic involuntary movements, muscular weakness, and emotional disturbances . Neurologic examination fails to reveal sensory losses or involvement of the pyramidal tract. The movements frequently are more marked on one side, are occasionally unilateral (hemichorea), and cease during sleep. Muscle weakness is best demonstrated by asking the patient to squeeze the examiner’s hands. The pressure of the patient’s grip variably increases and decreases, a phenomenon known as relapsing grip or “milkmaid’s sign.” Diffuse hypotonia may also be present. Emotional changes manifest with outbursts of inappropriate behavior, such as crying and restlessness. In rare cases, psychologic manifestations are severe and can result in transient psychosis. Chorea can present up to 8 months after streptococcal infections, with a longer latent period than most other rheumatic manifestations . Some patients with chorea have no other clinical symptoms, but nevertheless should undergo an evaluation for carditis with an echocardiogram.
Erythema marginatum is an evanescent, pink or faintly red, non-pruritic rash involving the trunk and occasionally the limbs, but not the face . The lesion extends centrifugally with return of the skin in the center to a normal appearance. The outer edge of the lesion is well-demarcated; the inner edge is diffuse. The lesion is also known as “erythema annulare” since the margin of the lesion is usually continuous, making a ring. Individual lesions may appear, disappear, and reappear in a matter of hours, with a hot bath or shower making them more evident in some instances. Erythema marginatum usually occurs early in the course of ARF in patients with acute carditis, but may persist or recur when all other manifestations of disease have disappeared . Cases have been reported in patients with chronic carditis as well . In some cases, the lesions are first noticed late in the course of the illness or even during convalescence.
Subcutaneous nodules in ARF are firm, painless lesions ranging from a few millimeters to 2 cm in size. The nodules are usually located over a bony surface or prominence, or near tendons (usually extensor surfaces), and are usually symmetric. The overlying skin is not inflamed and usually can be moved over the nodules . The number of nodules varies from a single lesion to a few dozen, with the average number being three or four. Rheumatic subcutaneous nodules generally appear after the first few weeks of illness and usually in patients with relatively severe carditis. Typically, nodules are present for 1 or more weeks and rarely persist for more than a month. In contrast to the nodules of rheumatoid arthritis, nodules of ARF are smaller and more short-lived. Though the elbows are involved most frequently in both rheumatic fever and rheumatoid arthritis, rheumatic fever nodules occur most commonly on the olecranon, whereas rheumatoid nodules usually are found 3 to 4 cm distally. In more recent outbreaks of ARF, nodules have been the least common manifestation .
Rheumatic heart disease is the most severe sequelae of ARF. It usually occurs 10 to 20 years after the original illness and is the most common cause of acquired valvular disease in the world [53, 54]. The mitral valve is more commonly involved than the aortic valve. Mitral stenosis, caused by severe calcification of the mitral valve, is the classic finding in rheumatic heart disease. The incidence of rheumatic heart disease in patients with a history of ARF is variable. Generally, valvular damage manifesting as a murmur later in life is likely to occur in about 50 % of patients with evidence of carditis at initial presentation [55, 56]. A rare sequela associated with recurrent episodes of ARF with polyarthritis is Jaccoud arthropathy, a chronic arthropathy that involves the hands and/or feet, in which the deformities are usually painless, correctable, and do not cause functional impairment .
Diagnostic evaluation includes studies to establish the diagnosis of GAS infection, evaluate acute-phase reactants, and assess cardiac function. Streptococcal pharyngitis may be diagnosed in one of the following ways: (i) positive throat culture for group A beta-hemolytic streptococci, (ii) positive rapid streptococcal antigen test, and/or (iii) elevated or rising anti-streptolysin O (ASLO) antibody titer. Throat cultures are negative in about 75 % of patients by the time manifestations of rheumatic fever appear . ASLO titers vary with age, season, and geography . Healthy children of elementary school age can have titers of 200–300 Todd units/mL, while asymptomatic pharyngeal strep carriers tend to have very low titers (only slightly above detectable). Following streptococcal pharyngitis, the antibody response peaks at 4 to 5 weeks, which is usually during the second to third week of rheumatic fever. Antibody titers fall off rapidly in the following months and after 6 months have a slower decline. Hence, it may be beneficial to collect one specimen when the diagnosis of ARF is first suspected and another 2 weeks later.
About 80 % of patients with documented ARF demonstrate a rise in ASLO titer, although this is not used as a measure of rheumatic activity. A negative ASLO titer should prompt commercial testing for other anti-streptococcal antibodies such as anti-DNAse B (detectable for 6 to 9 months following infection), streptokinase, and anti-hyaluronidase. About 90 % of patients with documented ARF have positive findings if two antigens are evaluated; about 95 % have positive findings if three antigens are evaluated.
Acute-phase reactants, such as serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are invariably elevated during ARF. CRP or ESR is useful for monitoring “flares” of inflammation as treatment is tapered. A normal result obtained a few weeks after discontinuing anti-rheumatic therapy suggests that the course of the illness is complete (unless chorea appears). The CRP may be more useful since it typically normalizes over a matter of days once an episode of acute inflammation has resolved, while the ESR may stay elevated for up to 2 months after a transient inflammatory stimulus. Other manifestations in ARF include a mild normochromic, normocytic anemia of chronic inflammation. Suppressing the inflammation usually improves the anemia, and iron therapy generally is not indicated. Complement levels are usually normal in ARF. In contrast, hypocomplementemia is typically observed in the setting of post-streptococcal glomerulonephritis.
There has been some speculation that some cases of arthritis occurring after a streptococcal infection may not be caused by ARF, but rather, post-streptococcal reactive arthritis (PSRA) [59–63]. Several observations support the notion that PSRA is a separate disorder [64, 65]. Firstly, the latent period between the antecedent streptococcal infection and the onset of migratory arthritis is shorter (1 to 2 weeks) than the 2 to 3 weeks usually seen in classic ARF. Secondly, the response of the arthritis to aspirin and other non-steroidal medications is poor in comparison to the dramatic response seen in classic ARF. Next, evidence of carditis is not seen in these patients and the severity of the arthritis is quite marked. Finally, extra-articular manifestations, such as tenosynovitis and renal abnormalities, often are seen in these patients and acute-phase reactants tend to be lower than in the setting of ARF.
However, the dilemma remains that these patients may in the end actually have ARF, with the above observations being explained by other factors. An unusual clinical course should not be sufficient to exclude the diagnosis of ARF. Migratory arthritis without evidence of other major Jones criteria, if supported by two minor manifestations, should still be considered ARF, especially in children. Clearly defining this reactive arthritis as a rheumatic fever variant has important implications for secondary prophylactic treatment, and some believe that PSRA is a benign condition without need for prophylaxis . In contrast, both the 1992 guidelines and the 2002 update concluded that although the relationship between PSRA and ARF remains unresolved, patients who fulfill the Jones criteria should be considered to have ARF [58, 43]. For those patients who do not fulfill the Jones criteria, the diagnosis of PSRA should be made only after excluding other rheumatic diatheses, such as Lyme disease and rheumatoid arthritis.
Treatment of GAS pharyngitis (adult dosages and regimens shown) (adapted from reference )
aOral penicillin V—500 mg two to three times a day for 10 days
Intramuscular penicillin, single dose—penicillin G benzathine 1.2 million units
Amoxicillin—875 mg twice a day or 500 mg three times a day for 10 days
Cephalexin—500 mg twice a day for 10 days
Alternative regimens if severe hypersensitivity to beta-lactam antibiotics exists:
Azithromycin—500 mg on day 1 followed by 250 mg daily on days 2 through 5
Clarithromycin—250 mg twice a day for 10 days
Clindamycin—450 to 600 mg orally three times daily for 10 days
Patients with severe carditis (significant cardiomegaly, congestive heart failure, and/or third-degree heart block) should be treated with conventional therapy for heart failure. Valve surgery may be necessary when heart failure due to regurgitant lesions cannot be managed with medical therapy alone [66, 67]. Surgical outcomes are generally better if valve surgery can be performed when carditis is quiescent . Valve repair, if feasible, is preferred over valve replacement since repair avoids the need for long-term anticoagulation associated with mechanical valves and the long-term risk of deterioration of a bioprosthesis .
Aspirin (80 to 100 mg/kg per day in children and 4 to 8 g/day in adults) is the major anti-inflammatory agent for relief of symptoms due to ARF. Aspirin levels can be measured, with 20 to 30 mg/dL being the therapeutic range. The efficacy of other anti-inflammatory drugs in the setting of active rheumatic carditis remains unclear [68, 55, 69–71]. A meta-analysis of eight randomized trials including 996 patients with ARF found no significant difference in the risk of cardiac disease at 1 year between the corticosteroid-treated and aspirin-treated groups . No reduction in the risk of heart valve lesions was observed with corticosteroids or intravenous immunoglobulin . Anti-inflammatory therapy should be continued until all symptoms have resolved. Normalization of inflammatory markers, such as ESR and CRP, can be utilized as biomarkers of resolution. The rash associated with ARF is transient and does not require any particular treatment, although anti-histamines may alleviate any associated pruritus.
Prevention of initial and recurrent attacks of rheumatic fever depends on effectively treating GAS pharyngitis [72, 10]. Prevention of an initial episode of rheumatic fever (primary prevention) is accomplished by prompt diagnosis and antibiotic treatment. Appropriate antibiotic treatment of streptococcal pharyngitis prevents ARF in most cases . However, at least one third of ARF episodes occur in the setting of inapparent streptococcal infection . For secondary prevention, patients who have had an episode of ARF and develop subsequent GAS pharyngitis are at high risk for a recurrence of rheumatic fever, with progression in severity of rheumatic heart disease from the initial episode. The most effective method to limit progression of rheumatic heart disease severity is prevention of recurrent GAS pharyngitis. As a consequence, prevention of recurrent rheumatic fever (secondary prevention) requires continuous antimicrobial prophylaxis, rather than recognition and treatment of acute GAS pharyngitis episodes. Continuous prophylaxis is warranted for patients with well-documented history of rheumatic fever (including cases with Sydenham chorea as the sole manifestation) and those with definite evidence of rheumatic heart disease.
The optimal duration of antibiotic prophylaxis following ARF remains unclear. Patients who have had rheumatic carditis (with or without valvular disease) are at relatively high risk for recurrent carditis and are likely to sustain increasingly severe cardiac involvement with each recurrence [75, 76]. Therefore, in general, prophylaxis in the setting of carditis should continue until the patient attains young adulthood (21 years of age), which is usually 10 years from an acute attack with no recurrence [77, 78]. This approach was evaluated in a Chilean study of 59 patients with history of ARF judged to be at relatively low risk for recurrence of ARF . Among patients with history of ARF without carditis, prophylaxis was discontinued after 5 years or at age 18 (whichever was longer). During 3,349 patient-months of follow-up, only two ARF recurrences were observed (0.7 per 100 patient-years). These data suggest that ARF prophylaxis can likely be discontinued safely in young adults judged to be at low risk for recurrence who are maintained under careful prospective surveillance.
Choice of antibiotics
Secondary prophylaxis for rheumatic fever (adult dosages and regimens shown) (adapted from reference )
aIntramuscular penicillin every 4 weeks—penicillin G benzathine 1.2 million units
Oral penicillin V—250 mg twice a day
Sulfadiazine—1,000 mg once a day
Alternative regimen if severe hypersensitivity to beta-lactam antibiotics exists:
Azithromycin—250 mg daily
ARF remains one of the few autoimmune disorders known to occur as a result of a specific pathogen. It remains a chronic and serious consideration in many parts of the developing world, and as a result, the importance of early diagnosis and treatment is paramount. Though joint manifestations can be migratory, transient, and self-limiting, cardiac sequelae have the potential for being chronic and life-threatening. The recent identification of an increased percentage of D8/17+ B cells appearing in a cohort of individuals at special risk of contracting ARF may provide an opportunity to identify early on those who may benefit from any future vaccinations for GAS that are developed, as well as increased surveillance and early, effective antibiotic strategies. Further research into ARF as a paradigm for microbial-induced autoimmunity via molecular mimicry has enormous ramifications for advancing the field of autoimmunity and rheumatic diatheses in particular. Indeed, this may provide an invaluable roadmap in further elucidating the etiology of other inflammatory diseases in which a potential, offending pathogenic trigger has yet to be identified.
Conflict of interest
There are no relevant conflicts to disclose by any of the authors.