Rheumatic fever is an acute, diffuse, and non-suppurative inflammatory disease that occurs in susceptible individuals as a late complication after an untreated pharyngotonsillitis, the infection itself sometimes being asymptomatic. It is caused by a group A β-haemolytic S treptococcus , specifically, Streptococcus pyogenes . The process is triggered by an inadequate immunological response, both humoral and cellular. There are four distinct phases characterizing the disease. The initial streptococcal pharyngotonsillitis is followed by latent period, and then by the acute and chronic phases. The chronic phase is also known as rheumatic heart disease, when the cardiac lesions remain as sequels of the acute phase. The disease has the potential to involve the heart, joints, brain, and subcutaneous and cutaneous tissues. Cardiac injury is the most important manifestation, and it is the injuries to the heart which produce its clinical, social, and economic impact.
Both rheumatic fever and chronic rheumatic heart disease continue to pose serious concerns with regard to health in many parts of the world, and present a significant challenge for those involved in providing health care. In developed countries, although its incidence has been markedly reduced since the 1950s, rheumatic fever remains a risk because of its potential for resurgence. 1 The disease has not yet been completely eradicated. As has been pointed out, prevention will be less than optimal until the pathogenesis of the disease has been totally elucidated. 2,3 In developing countries, this preventable disease remains both socially and clinically devastating, with significant rates of morbidity and mortality. The acute episodes of rheumatic fever are still a cause of death in childhood, and the chronic disease is the most important cause of acquired cardiac disease in children, adolescents, and young adults, besides being considered the most frequent condition necessitating valvar surgery in adults. The repercussions of the disease involve patients of all ages, since the valvar sequels can be carried throughout life. The children and adolescents, who are most frequently admitted to hospital with acute episodes, are the same group of patients who, after the fourth decade of life, form the largest group when analysis is focused on invasive intervention and death. The economic impact must also be considered, not only with regard to the financial cost of clinical and surgical treatments, but also relative to the loss of productivity as the result of disability acquired at an early age.
HISTORICAL BACKGROUND
From the historical perspective, the clinical manifestations of rheumatic fever had been well described prior to the recognition of the complete syndrome. Arthritis had been mentioned since the days of Hippocrates, but only in the 17th century did the French doctor Guillaume de Baillou distinguish acute articular rheumatism from the other forms of rheumatism. In the posthumous edition of the Liber de Rheumatismo et Pleuritide dorsali , published in 1642, he was the first author to use the term rheumatism to describe the acute form of arthritis. Thomas Sydenham, in England, in his book Observationes medicinae, published in 1676, provided an accurate description of the acute migratory polyarthritis as distinct from gout. He also described, 2 years later, St Vitus’s dance, another major manifestation of rheumatic fever, which we now call Sydenham’s chorea. Important discoveries in cardiac pathology were made in the 18th century. Warty vegetations, and thickening of the valvar leaflets as an isolated postmortem feature, were recognised in 1709 by Giovanni Maria Lancisi, while Raymond Vieussens, in 1715, contributed a description of mitral stenosis, with calcification of the leaflets. Giovanni Battista Morgagni, in the tome De Sedibus , published in 1761, dealt with lesions of all cardiac valves, and described endocardial vegetations. The association of cardiac disease and rheumatism was noted by Morgagni, but deemed coincidental. It was Richard Pulteney, in the same year, who on the basis of his observation of pathology called attention to the association of cardiac involvement and acute articular rheumatism. Matthew Baillie, nonetheless, in his tome entitled A Series of Engravings Tending to Illustrate the Morbid Anatomy of Some of the Most Important Parts of the Human Body, gave credit for this recognition of a causal relationship between cardiac disease and rheumatism to David Pitcairn. The first full account of the pathology of rheumatic fever was then provided in 1808 by Dundas, who underscored the relationship of the cardiac features to rheumatism. In 1812, a detailed report was given in On Rheumatism of the Heart by William Charles Wells, who in 1813 also described the subcutaneous nodules. This author confirmed that, although Pitcairn had failed to provide a written record, he had already, by 1788, established the association between rheumatism and cardiac lesions. The introduction of the stethoscope by René Laennec, in 1816, facilitated the study of cardiac diseases, but not until 1832 did Jean-Baptiste Bouillaud provide a detailed account of rheumatic cardiac disease, correlating the clinical events with the post-mortem findings. In his treatise Traité clinique des maladies du coeur he introduced the term endocarditis and clarified the clinical picture, giving an accurate account of the cardiac involvement and other manifestations in patients with rheumatic fever. The eponym maladie de Bouillaud for rheumatic fever recognised his great contribution, distinguished by its exceptional accuracy and clinical significance. In the same year, James Hope, as had already been pointed out by Wells and Dundas, detailed and emphasised the association of acute pericarditis with rheumatic fever. Cheadle, in 1886 described the complete syndrome, emphasising the set of clinical manifestations we currently recognise as major criterians, namely, carditis, arthritis, chorea, subcutaneous nodules, and erythema marginatum. Subsequently, the pathognomonic and distinctive microscopic nodules of rheumatic carditis were described in 1904 by Ludwig Aschoff. 4–8
The first report of a possible connection between a bacterial infection and rheumatic fever had been suggested by Mantle in 1887, but it was not until 1930 that the causal relationship between infection by the β-haemolytic streptococcus and rheumatic fever was established. 9–11 From then on, data about the disease was gathered in many other fields. Todd, in 1932, 12 introduced a method for measuring one of the antibodies developed by the human body after the contact with the bacteria. Then, 1 year later, Lancefield 13 classified the streptococcus into five distinct groups. Subsequently, 14 continuous administration of sulphanilamide was shown to prevent recurrences, followed in 1950 15 and 1951 16 with demonstration that adequate treatment of the streptococcal pharyngitis with penicillin prevented the disease.
As early as 1944, Thomas Duckett Jones had proposed a set of clinical and laboratorial data to guide and reduce the over-diagnosis of rheumatic fever. 17 The Jones criterians were subsequently modified and updated by the Committee of the American Heart Association. 18–22 They have long been recognised as guidelines for the diagnosis of the first episode of the acute phase. The knowledge of the action of antibiotics in preventing the disease, and the systematisation of the diagnosis by means of the important Jones criterions, heralded a new era of studies.
EPIDEMIOLOGY
Rheumatic fever has a universal distribution, albeit that significant differences in the rates of incidence and prevalence depend on the interaction of characteristics of the aetiologic agent and its human host, besides environmental and socioeconomic conditions. Due to the causal relationship of streptococcal pharyngotonsillitis and rheumatic fever, the epidemiology of the two diseases is closely related. Rheumatic fever is more frequent among children and adolescents between the ages 5 and 15, and has a peak of incidence around the ages of 8 to 9 years. These ages coincide with the peak of streptococcal pharyngotonsillitis in school-aged children, this infection being less common in late adolescence and in adults. Likewise, rheumatic fever is uncommon in children under 4 years of age, and exceedingly rare under the age of 2. 23–25 The increased number of young patients can be attributed to the anticipation of the school years. Data from Brazil revealed that 2.5% of patients had their first episode under the age of 3. 26 In a study from India, Aschoff bodies were found in one-tenth of autopsied cases, the majority from patients between 16 and 40 years of age, indicating a recent attack of carditis. 27 Under special circumstances, such as focal epidemics of streptococcal infections in military populations or closed institutions, the incidence of rheumatic fever can increase in adults. 28,29
Rheumatic fever occurs in all populations, and shows equal frequency in both genders. The exception is Sydenham’s chorea, which is more common in females, and is hardly ever seen in males after puberty. 30 Rheumatic fever has usually been reported as a disease of the temperate climates, but currently it is more prevalent in warm tropical climates, especially in developing countries. Similarly, the influence of seasonal variation in the rates of incidence is now less defined, but in general follows that of streptococcal infections, which are most commonly observed in late winter and early spring. 31,32 The disease is reputed to be more frequent in urban centres than in rural communities, but this is probably due to over-crowding. 33 Although data thus far is inconclusive, it has been suggested that there is an increased susceptibility to rheumatic fever in certain ethnic groups. The aboriginals of Australia’s Northern Territory, and the Polynesians, both from rural areas, show a markedly increased incidence of the disease. 31,34 In Hawaii, wide differences in the prevalence of chronic rheumatic heart disease have been documented in the Samoan schoolchildren when compared with the Caucasian Hawaiians 35 Similarly, higher frequencies of rheumatic fever and chronic rheumatic heart disease have been found in the Maori population of New Zealand, 36 and among black schoolchildren in South Africa. 37 Many factors, however, can overlap and interfere in the calculations of the incidence of rheumatic fever and the prevalence of chronic rheumatic heart disease, since different rates can be found under diverse environmental conditions for any given population. In this context, besides the role played by the bacteria and human host, other factors, such as differences in patterns of living condition and streptococcal exposure, in addition to quality of and access to health care, are important and can impact the geographical distribution of the disease, as well as the severity of its sequels.
All over the world, pharyngotonsillitis is one of the most prevalent infections caused by the β-haemolytic streptococcus. It accounts for up to one-third of the throat infections in children, and up to one-tenth in adults 29,38 Although the streptococcal infections are very frequent, only a few individuals develop rheumatic fever. It is calculated that, under endemic conditions, 0.3% of untreated infections, and 3% in epidemics, will lead to a first episode of rheumatic fever. 39 In spite of a marked decrease of rheumatic fever in the developed countries, the incidence of infections of the upper respiratory tract by the group A Streptococcus has not been reduced. Even considering that the strains of bacterium producing the infection are often relatively attenuated, more virulent strains can change the characteristics of the infections and their sequels. Emergence of mucoid strains was observed at the close of the 20th century in the United States of America and Western Europe, showing an apparent temporal association with the increase in frequency and severity of the systemic invasive streptococcal infections of the skin and soft tissues such as toxic shock syndrome, sepsis, myositis, and necrotizing fasciitis. The simultaneous resurgence of rheumatic fever in the United States is also highly suggestive of a relation with the appearance of more virulent group A strains. 40–43
Recurrences of rheumatic fever, as a consequence of inadequate prophylaxis, are more frequent in developing countries, where predisposing factors to streptococcal infections still persist. The risk of subsequent attacks increases with the number of previous attacks, with the continued exposure to streptococcal infections, and falls with age. The recurrence rate is higher during the first 5 years subsequent to the acute episode, particularly in the first 2 years. Likewise, the risk of other attacks is higher in patients receiving oral secondary prophylaxis when compared to parenteral medication. The clinical features of subsequent attacks show a tendency to mimic those seen in the initial attack. 44 Prospective follow-up to identify predictors of significant chronic rheumatic valvar disease 45 shows that almost half recurrences occur in the first 2 years of the disease ( Fig. 54A-1 ).
In spite of a decline in both frequency and severity, rheumatic fever still remains a risk. In 1994, it was estimated by the World Health Organization that a total of 12 million individuals were affected by rheumatic fever and rheumatic heart disease worldwide. 1 In developing countries, the incidence of rheumatic fever is still very high, with a wide variation from 1.0 to 254 for each 100,000 of the population. 1,31,35 More than 336,000 cases of rheumatic fever occur in children and adolescents aged from 5 to 14. 46 Although a downward trend has been noticed worldwide, the rates in some areas are similar to those found in developed countries at the turn of the 20 century. 47,48 Investigations in the aboriginal communities in Northern Australia suggest a lifetime risk for having rheumatic fever to be as high as 5% to 7%. 34
Rheumatic fever, nonetheless, has now become rare in developed countries, where the incidence is estimated at below 1 for each 100,000 of the population. 49 The reasons for this decline of up to 100 fold over the last 50 to 60 years are not completely understood. 50 Several factors are involved, but none can explain this decline when considered in isolation. 28,43,51,52 It has been attributed to the decreasing rheumatogenic potential of group A streptococcal strains, and to changes in susceptibility of the human host, besides the modifications in the environment. In this context, the increased nutrition and better living conditions, as a consequence of improvements in social and economic standards, have contributed to reduce the spread of the infecting agent. Other determining factors are the better availability of health care, and the advent of antimicrobial agents. The widespread use of antibiotics has accelerated the decrease of the disease, in terms of both morbidity and mortality. A fourfold acceleration of the decline was observed after the introduction of penicillin and other antibiotics. 53 Furthermore, the establishment of stricter clinical criterions enhanced the accuracy of the diagnosis, and consequently reduced over-diagnosis. Technological advances in laboratory diagnosis also improved the differential diagnosis from other cardiac diseases, such as congenital structural diseases, myocarditis, and mitral valvar prolapse, which in a clinical setting had often been misdiagnosed as rheumatic fever.
Despite the apparent control, the disease had resurged in the United States of America by the mid-1980s. During the last two decades of the 20th century, outbreaks were reported in distinct geographical regions of the country among different age groups, mainly schoolchildren and young adults in military bases. 42,52,54 The outbreaks showed an unexpected pattern, occurring among white, middle-class patients with ready access to health care and antibiotic therapy. Between 1985 and 1988, a national survey was performed in cities of 24 states of the United States, and showed evidence of an increase in the number of cases from 5 to 12 times when compared to the previous decade. 40 Isolated reports of increased frequency of rheumatic fever also came from Europe. 55–57
No isolated factor can be held responsible for the epidemiological changes in both the disappearance and the reappearance of rheumatic fever, and the underlying reasons have still to be completely explained. It has been questioned whether the outbreaks represented a true risk of return of the disease, or simply were an oscillation in its declining profile of incidence. 51 As was pointed out by Kaplan and Markowitz, the reasons for the virtual disappearance of rheumatic fever have not yet been sufficient to control the disease. 3,52
AETIOLOGY AND PATHOGENESIS
A broad range of clinical manifestations may occur after a streptococcal infection, varying in severity from mild and superficial dermal infection to necrotizing fasciitis or severe septicaemia. Non-suppurative sequels depend on a delayed immune-mediated host response, and include rheumatic fever, acute glomerulonephritis, and reactive arthritis. As we have already discussed, the association between streptococcal pharyngotonsillitis and the subsequent development of rheumatic fever was recognised in the first half of the twentieth century, but the precise pathogenesis of the disease has still not been completely elucidated. Major advances in the understanding of the pathogenic mechanisms have only recently been achieved from immunological, molecular biologic, and genetic studies. Susceptibility to rheumatic fever depends on the interaction between the streptococcus and host factors, influenced also by environmental conditions. Both humoral and cellular delayed immune responses to the streptococcal throat infection take part in the process. Their extension determines the severity of the disease in one individual. In particular, autoimmunity against the tissues of the host plays a key role in the pathogenesis and progression of the disease. Molecular mimicry between streptococcal antigens and several human tissues, such as cardiac valves and myosin, cartilage, and synovial and cerebral proteins has been proposed and proved to be the basic mechanism triggering autoimmunity. Bacteria are absent from the acute and chronic tissue lesions of rheumatic fever.
STREPTOCOCCUS AND ITS ANTIGENS
Streptococcus pyogenes , or the group A Streptococcus , is a Gram-positive extracellular bacterium covered by an outer layer of hyaluronic acid. Its cell wall is composed of repeating units of N-acetyl- d -glucosamine carbohydrates linked to a rhamnose polymer backbone ( Fig. 54A-2 ).
The classification of the microorganism in serogroups is based on studies that distinguished by serology the bacterial mural polysaccharides, giving groups A, B, F, and G. The concept of different bacterial strains causing disease in specific target organs emerged from decades of epidemiological studies, revealing serotypes of group A Streptococcus as having a strong tendency to cause pharyngotonsillitis, and others to be associated with impetigo. 41 Although different serogroups may also cause throat infections, there is no evidence linking bacteria from the remaining serological groups with the development of rheumatic fever. 1
The M, T, and R proteins on the bacterial cell surface, along with lipoteichoic acid, are involved in the adhesion of the bacteria to the host epithelial cells, and in their ability to resist phagocytosis in the human host. 1,58 (see Fig. 54A-2 ). Thus far, it has proved possible to identify more than 100 M serotypes, based on the antigenic variation of the N-terminal portion. 58 The M protein is particularly important in determining the virulence of the microorganism, since it promotes avid adherence to host tissues. Moreover, it is the M protein that shares structural homology with certain α-helical human molecules such as myosin, tropomyosin, laminin, vimentin, keratin, and laminin, thus forming the basis for the immune-mediated post-infectious sequels. Laminin is an extracellular matrix protein present in the cardiac valves, being secreted by the endothelial cells that line them.
The M protein molecule itself has a variable composition ( Fig. 54A-3 ). As explained, its N-terminal portion contains the A-repeat region that produces antigenic variation. 41 The B-repeat region also varies from serotype to serotype, while the C-repeat regions contain highly conserved epitopes. Classification of the streptococcus into class I or class II depends on whether their M protein reacts with a monoclonal antibody that targets epitopes in the C-repeat region. 1 While class I strains are predominantly negative for the production of serum opacity factor, and are recognised as rheumatogenic, class II strains produce the serum opacity factor, bind fibronectin, and are usually associated with production of glomerulonephritis. 46 Serotypes, such as M types 1, 3, 5, 6, 14, 18, and 24, have also been associated with the development of rheumatic fever. An alternative means of serotyping is to sequence the gene encoding the 5′ terminal end of the M protein. A great range of genetic diversity has been shown in this fashion in isolates recovered from many different geographical locations. 32,59,60 The identification of these so-called emm types present in a community at the time of an outbreak of rheumatic fever permitted recognition of the types most commonly associated to the disease, and revealed emm types 1, 3, 5, 6, 14, 18, 24, 17, and 29 to be rheumatogenic. 61 This concept of rheumatogenicity, however, has recently been challenged, since some types frequently associated with acute rheumatic fever are infrequently found in several communities with high burdens of the disease, where new, non-M antigen typeable microorganisms have been identified. 46,62 These new types probably result from genetic recombination between different strains of the group A Streptococcus . It is not surprising that a clear distinction between the rheumatogenic and non-rheumatogenic strains of the group A Streptococcus does not exist in areas of the world with high rates of superficial infections, since multiple genetically distinct strains circulate at the same time. This broad genetic diversity has important implications in the development of a vaccine against streptococcal infections.
THE HUMAN HOST
Alleles of the Human Leucocyte Antigen Associated with Rheumatic Fever
Considering that less than 3% of the patients with acute streptococcal pharyngotonsillitis develop rheumatic fever, it is reasonable to suggest that the genetic predisposition of the individual plays an important role in the pathogenesis of the disease. In the 19th century, it was suggested that both rheumatic fever and rheumatic heart disease were hereditary, 46 possibly transmitted in autosomal recessive fashion. Further studies on the determinants of host susceptibility indicated that the immune response to the streptococcal infection is genetically controlled. More recently, molecular biologic techniques have identified an association between the disease and some alleles of the major histocompatibility complex. These class II human leucocyte antigen molecules are expressed on the surface of antigen-presenting cells, such as macrophages, dendritic cells, and B cells. Together with the bound peptide antigen, they trigger the activation of T lymphocytes. Several such alleles have been associated with rheumatic fever in different countries ( Table 54A-1 ). While DR7 is the allele most frequently associated with rheumatic fever in Brazil, Turkey, and Latvia, the DR4 allele is found in American-Caucasian, Indian, and Saudi-Arabian patients. Recently, in Mexican and Brazilian patients with rheumatic heart disease, 63,64 some alleles of the tumour necrosis factor–α, also located in the region of the major histocompatibility complex, were described with increased frequency. A possible explanation for the frequent association of certain alleles with the development of rheumatic fever and rheumatic heart disease is that these molecules might cause inappropriate activation of the T cells, resulting in autoimmunity.
| HLA Class II Allele | Country |
|---|---|
| DR1 |
|
| DR2 |
|
| DR3 |
|
| DR4 |
|
| DR5 | Turkey |
| DR6 |
|
| DR7 |
|
| DR9 | USA |
| DQA1∗0104 | Japan |
| DQB1∗05031 | Japan |
Interactions Between Host and Pathogens
It is well recognised that the molecular mimicry between some antigens present on the surface of group A Streptococcus and specific human tissues triggers the autoimmune response causing acute rheumatic fever. Structural similarities between the streptococcal M protein and myosin are the key for the development of acute carditis. On the other hand, valvar lesions are triggered by immune reactions against human proteins such as laminin, an α-helical coiled-coil molecule present in the valvar subendothelium. Both the humoral and cellular arms of the immune response take part in the host response against these self-proteins sharing some homology with the streptococcus.
Humoral Response
After the adherence of the bacteria to the host cells, the processes of colonisation and invasion supervene, inducing the production of type-specific antibodies by B-derived mononuclear cells, leading to opsonisation and phagocytosis. As pointed out recently, 58 heart-reactive antibodies were first described by Calveti in 1945. The recognition of cross-reactive streptococcal epitopes and human antigens, mainly myosin and laminin, led to a great advance in the studies directed to the knowledge of the mechanism of the disease.
Cross-reaction between antibodies to cardiac valvar tissue and the N-acetylglucosamine of the polysaccharide from group A Streptococcus has been clearly demonstrated. 41,65,66 Additionally, some studies have shown that the cross-reacting antibodies bind to the endocardial surface of valves, up-regulating the local expression of adhesion molecules like vascular cell adhesion molecule-1, which facilitates infiltration of inflammatory cells inside the valvar leaflets, which are avascular, leading later to scarring 67 ( Fig. 54A-4 ). The pathogenic mechanism responsible for the Sydenham’s chorea present in some patients with acute rheumatic fever is also dependent on the cross-recognition of neuronal tissue proteins by antibodies directed to the N-acetylglucosamine of the streptococcus. 68
Cellular Response
T lymphocytes of subsets CD4 and CD8 are the main mediators of the myocardial and valvar lesions of rheumatic fever and rheumatic heart disease, participating in a delayed-type hypersensitivity reaction (see Fig. 54A-4 ). In the acute phase, the pathognomonic histological feature is the Aschoff body, a granulomatous lesion found in both the myocardium and in valvar leaflets, and composed of T lymphocytes, B lymphocytes, macrophages, large mononuclear cells, and polymorphonuclear leucocytes. The nodules develop as a result of cellular infiltration through the endothelium. The presence of activated macrophages inside the bodies is consistent with an immune response of the CD4+ T helper 1 type. 69
Proinflammatory cytokines, such as tumour necrosis factor–α and interleukin-1, are over-produced by peripheral blood mononuclear cells in patients with rheumatic fever. They are also predominantly expressed by mononuclear inflammatory cells inside the chronic valvar lesions, indicating their local role even in the chronic phase of the disease. Cytokines are considered important second signals after infections, triggering effective immune responses in most individuals, but in the context of autoimmune diseases they induce a deleterious response. Differences in the pattern of cytokine production were observed between inflammatory cells derived from valvar and myocardial tissue from patients with rheumatic fever. 70 These findings reinforce the putative role of these regulatory cytokines in the myocardial healing, but not in valves, where the damage is progressive and permanent. The sparing of the right-sided cardiac valves in most cases of rheumatic fever is usually attributed to the lower pressure and shear stress to which they are usually submitted compared to the left-sided valves. Quadrivalvar rheumatic disease has been reported only rarely, and usually then in patients with congenitally malformed hearts. 71 The location of the acute valvar lesions along the lines of closure of the leaflets corroborates the hypothesis that lesions occur at places that are most liable to trauma.
MORPHOLOGY OF THE ACUTE CARDIAC AND EXTRACARDIAC LESIONS
The sequence of immunological events described above culminates in the development of acute rheumatic fever, which presents as exudative and proliferative inflammatory reactions in the connective tissue of the affected organs. These lesions are more distinctive within the heart, but involve also the joints, subcutaneous tissue, brain, and vessels of the lung. Basically, they are characterised by mononuclear inflammatory cells around a focus of fibrinoid necrosis. In the heart, the pericardial, myocardial, endocardial layers are all affected, hence there is a pancarditis. The histological landmark of acute rheumatic fever is the Aschoff body (see Fig. 54-8 ).
Grossly, the pericarditis is characterised by the deposition of a serofibrinous exudate, giving the so-called bread-and-butter appearance. Acute valvar lesions are found as small vegetations of 1 to 2 millimetres along the lines of closure on the atrial aspect of the atrioventricular valves, and on the ventricular surface of the arterial valves ( Fig. 54A-5 ). These small verrucous lesions may extend to the tendinous cords of the atrioventricular valves, and in rare instances may be associated with cordal rupture, causing severe valvar regurgitation and cardiac failure. Microscopically, the vegetations are composed of fibrin thrombus overlying an area of fibrinoid necrosis of the valvar connective tissue. These areas of necrosis are surrounded by a dense inflammatory infiltrate, containing mononuclear cells and occasional giant cells. Presumably, the fibrin vegetations accumulate on the ulcerated endocardium in areas of extrusion of the damaged collagen ( Fig. 54A-6 ). Although the typical Aschoff bodies, pathognomonic of the disease and most commonly seen in the myocardium, are not usually found in valvar tissues, the acute valvar lesion transforms with time, showing inflammatory cells arranged in palisade around the central necrotic core. These lesions eventually heal, producing local fibrosis. Moreover, the adjacent tissue of the valvar leaflets is oedematous, and shows a diffuse non-specific mononuclear infiltrate. Neovascularisation is not a feature in this phase of the disease, but thin-walled blood vessels can be seen invading at the base of implantation of the leaflet.
In the case of a recurrent attack, the fibrin vegetations still appear on the same structures, but there are already valvar sequels, such as cordal fusion and thickening of the leaflets ( Fig. 54A-7 ). The relative frequency of valvar involvement correlates to the haemodynamic closing pressures, the decreasing order being mitral, aortic, tricuspid, and pulmonary.
Although myocardial involvement in acute rheumatic fever is typically called myocarditis, direct myocytic injury as it is observed in viral myocarditis is not a striking feature. Instead, the finding of multiple Aschoff bodies is the fingerprint of the disease. These granulomatous nodules are usually located in the connective tissue around small vessels ( Fig. 54A-8 ). They show fibrinoid necrosis surrounded by lymphocytes, 58 some plasma cells, and plump macrophages with abundant cytoplasm and a clear nucleus where a central wavy ribbon of condensed chromatin is observed. These are called Anitschkow cells, or caterpillar cells, the latter reflecting their appearance when cut longitudinally. Multi-nucleated macrophages may also be present, and receive the name of Aschoff giant cells. Aschoff bodies often appear in the myocardium about 4 weeks after the acute onset of rheumatic fever, and may remain in the tissue for as long as 3 to 6 months. Although the earliest lesions show prominent fibrinoid necrosis and inflammation, as described above, the life cycle of the nodule continues with a gradual decrease in the cellular content. The complete healing of those lesions takes the form of a fibrous scar around small myocardial vessels.
The role of myocarditis in the failure of the heart in acute rheumatic fever has recently been questioned, 72,73 since levels of troponin I are typically within normal limits, which indicates absence of direct damage to cardiomyocytes. Since most patients with heart failure have valvar dysfunction, mainly isolated mitral regurgitation or combined mitral and aortic regurgitation, this in itself could explain the congestive symptoms. Even without direct damage to the contractile cells, nonetheless, the myocardium in the setting of acute rheumatic fever is oedematous and, besides the Aschoff bodies, an interstitial mononuclear inflammatory infiltrate of variable intensity is a common finding. These features could disrupt the myocardial integrity, and possibly interfere with the cardiac function. Dilation of the mitral annulus is also a contentious topic. Some believe that valvar regurgitation precedes dilation of the chambers, while others argue that myocardial impairment comes first, since in the acute phase the leaflets are just mildly deformed by fibrin deposition. Since it is virtually impossible to be certain that a given episode of rheumatic carditis is the first, valvar regurgitation, when present in the context of an acute carditis, could always be the consequence of previous deformity of the leaflets. Another lesion considered characteristic of the acute phase is MacCallum’s patch. This is an endocardial lesion on the postero-inferior left atrial wall, frequently containing Aschoff bodies when examined histologically. This thickening, however, is more likely to be a jet lesion from mitral regurgitation than a specific rheumatic lesion. Although the diagnosis of acute rheumatic fever is usually made on clinical grounds, the endomyocardial biopsy is said to have value in diagnosis. Histological diagnosis, however, is based on the presence of Aschoff bodies. These structures were found, in one study, in less than one-third of patients with acute rheumatic fever, and only two-fifths of those with recurrent attacks. 74 This suggests that endomyocardial biopsy is not likely to add important diagnostic information.
DIAGNOSIS
Clinical Manifestations
Since the description provided by Cheadle in 1889, no modification has been incorporated into the clinical profile of rheumatic fever, characterised by its uniformity as a syndrome and by its diversity as a multi-system disease. The clinical presentation, with its variable pattern of symptoms and signs, is determined by the sites of involvement, by the time of appearance along the course of the acute attack, and whether the manifestations occur alone or in combination. Additionally, the clinical picture is also influenced by a wide range in severity of the individual manifestations.
The latent, or asymptomatic, period between the streptococcal infection and the onset of rheumatic fever lasts from 1 to 5 weeks, except for Sydenham’s chorea, which may take longer to appear. The acute episodes are time limited, ranging usually from 6 to 12 weeks, but sometimes as long as 6 months in those with severe carditis. All are at risk of recurrence following a subsequent untreated infection with the group A Streptococcus . The duration of the acute episode is similar in both the first episode and recurrences. 6
The diagnosis is made on a clinical basis. The supportive microbiological and serological laboratorial data is then used to characterise the underlying streptococcal infection, besides establishing the presence and resolution of the acute inflammatory process. No single symptom or sign is pathognomonic, nor are there specific laboratory tests. The diagnostic criterions formulated by Jones 17 have been revised over the past years. The reviews have clarified the categorisation of major and minor manifestations, and emphasised the importance of the laboratory evidence of the preceding infection by the group A Streptococcus . As a consequence, over-diagnosis has been reduced with provision of more detailed information and improved specificity. In addition, exceptions to the criterions were highlighted with the aim of diminishing the risks of under-diagnosis. The division between major and minor criterions was based on the specificity of the manifestations for the diagnosis, and not on their frequency or prognostic significance. 75 The five most characteristic clinical features constitute the major manifestations, namely, carditis, arthritis, chorea, subcutaneous nodules, and erythema marginatum, independent of their severity. Classically, arthritis and carditis, isolated or in combination, are seen most frequently. Chorea is less common, and the other major manifestations are rare ( Fig. 54A-9 ). The minor manifestations are mostly related to the underlying systemic inflammation. Although non-specific, these clinical and laboratory findings are frequent, and supportive of the diagnosis when accompanying a major manifestation. In the presence of arthritis, however, arthralgia cannot be considered as a minor manifestation. The combination of two major or one major and two minor manifestations, supported by evidence of preceding infection with the group A Streptococcus , indicates a high probability for the diagnosis of rheumatic fever 1,21 ( Table 54A-2 ).
| Major Manifestations | Minor Manifestations |
|---|---|
| Carditis | Clinical |
| Polyarthritis | Fever |
| Chorea | Arthralgia |
| Subcutaneous nodules | Laboratorial |
| Erythema marginatum |
|
| Evidence of a preceding group A beta-haemolytic streptococcal infection: elevated or rising streptococcal antibody titre or positive throat culture or elevated or rapid antigen test for group A streptococci (AHA 992) | |
The current guidelines are intended for the diagnosis of first attacks. Once other diagnoses are excluded, three situations—Sydenham’s chorea, indolent carditis, and recurrent episodes—are exceptions to the strict adherence to the Jones criterions. Since Sydenham’s chorea usually occurs as a late manifestation of the disease, the inflammatory process and the immunological response to streptococcal infection could have already subsided when this feature becomes evident, and laboratory evidence is seldom found. Similarly, patients with insidious onset of carditis can delay seeking medical attention. By the time of their clinical evaluation, the acute-phase reactants and levels of antistreptococcal antibodies may be normal. Faced with a reliable history of a previous episode of rheumatic fever, or established chronic rheumatic heart disease, the diagnosis of recurrence constitutes the third exception to use of the Jones criterions. Diagnosis may then be made in the presence of one major or several minor manifestations, along with supporting evidence of recent infection by the group A Streptococcus . In addition to the Jones criterions, other non-specific clinical findings may also be found during the course of the acute episodes. 1,21
Major Manifestations
Carditis
Carditis is the most serious manifestation, because only in the heart are the lesions potential causes of sequels, such as death during the acute attack or later. The pericardial and myocardial damages carry no long-term morbidity. Carditis in first episodes is more frequent in younger children, and depending on its severity, is characterised by murmurs related to regurgitation of the mitral and aortic valves, enlargement of the heart, pericarditis, and congestive cardiac failure.
Carditis is reported to be seen in up to three-fifths of first attacks, although more recent series have shown higher rates when echocardiography is included in the evaluation. 5,42,45,76 Carditis tends to appear early, and is usually diagnosed within the first 3 weeks of the acute episode. Different patterns of onset can be found. Clinical presentation with fever and arthritis of abrupt onset is observed in older children, with or without indistinct clinical cardiac findings. The involvement of the heart becomes more apparent later over the first 2 weeks of disease. More frequently in young children, the disease begins insidiously, with vague symptoms, slight fever, and a sallow complexion. These children can also present mild arthritic complaints, besides shortness of breath or chest pain. Cardiac findings are present at first examination, are commonly marked, and tend to progress to congestive cardiac failure. Another mode is a late appearance of carditis, concurrent with the manifestations of Sydenham’s chorea. This pattern probably represents a progression of a previously unrecognised mild cardiac involvement during the early stages of the acute attack. 6,44 Yet another pattern is that of subclinical, or silent, carditis. Mild cardiac involvement may not be clinically recognised in patients with isolated chorea or arthritis, the valvitis being demonstrated only by Doppler echocardiography.
The cardiac damage in the acute episode is characterised by pancarditis. The determinants of morbidity and mortality, nonetheless, are the degree and extent of endocarditis, represented by the lesions of the cardiac valves. Pericarditis is not common, being found in only one-tenth or less of the patients. 77,78 As with the myocardial participation, this is part of the active pancarditis, and is not found as a sole manifestation. When present, it is invariably associated with valvar dysfunction, so other causes should be investigated if valvar dysfunction is not recognised. Pericardial involvement is diagnosed by the presence of pericardial friction rub, effusion, distant heart sounds and chest discomfort or chest pain. The rub is heard as a scratching or grating sound over the praecordium, especially along the sternal border, and is heard in both phases of the cardiac cycle, having a to-and-fro character. It is less transient in rheumatic fever than in pyogenic infections. In the early stages, the friction rub may obscure the murmur of underlying valvar dysfunction, and the murmur becomes apparent only when the rub subsides. 76 In mild cases, the pericardial injury is sometimes an exclusive echocardiographic finding. Significant effusion is rarely found, and the rheumatic pericarditis does not result in constriction. Despite its low frequency, pericarditis has diagnostic value by providing evidence of an active disease.
Myocarditis has been diagnosed on the basis of signs such as abnormalities of first sound, protodiastolic gallop, cardiomegaly, and congestive cardiac failure. In spite of in the acute process histological and immunological evidences of the myocardial participation, nonetheless, more accurate assessment has provided new insights to the role played by both myocarditis and valvitis in the presentation of symptoms and heart failure. 79 Different from patients with other forms of myocarditis, the ejection fraction and shortening are usually normal in the first episodes. Markers of injury to the myocytes are insignificantly elevated. 72,73,80,81 Patients with congestive cardiac failure unresponsive to clinical treatment throughout the acute phase have shown rapid recovery after valvar surgery. 82 These observations support the notion that the valvar lesions are dominant in the clinical presentation of carditis. 79,83–85
Endocarditis is the diagnostic hallmark of carditis, being expressed by valvitis. The inflammatory process affects most frequently the mitral and aortic valves. Isolated aortic involvement, however, is rare. Involvement of the right-side valves is unusual. Valvar dysfunctions in the acute phase are represented by regurgitation. Obstructive lesions become established during the chronic phase, the process of cicatrisation taking time to develop. If stenotic lesions are found in the acute phase, this favours the diagnosis of recurrence.
Three murmurs are characteristic of the first acute episode, and they do not represent definitive valvar dysfunction. The apical murmur of mitral regurgitation is pansystolic, beginning with the first sound, and is heard maximally at the apex with the patient in the left lateral decubitus position. It is transmitted to the left axilla, and remains unchanged in both phases of respiration. It has a high-pitched blowing quality, with its loudness roughly proportional to the degree of valvar regurgitation. The Carey Coombs murmur is a low-pitched mid-diastolic murmur, beginning immediately after the third sound, finishing before the first sound, and usually of low intensity. The murmur is best heard at the apex, or just above it, by using the bell portion of the stethoscope applied lightly against the chest wall with the patient again lying in left lateral decubitus. This apical mid-diastolic murmur occurs when there is mitral regurgitation, is transient, and tends to disappear during the recovery from the acute episode. The mechanism is not completely understood. It has been attributed to the inflammatory process and its consequences in the mitral apparatus, besides the high velocity of flow into the dilated left ventricle. The third murmur, the basal diastolic murmur of aortic regurgitation, has a soft, high-pitched, decrescendo quality, and may be found early in the course of the disease. It is difficult to detect, and sometimes has an intermittent character. It is an early diastolic murmur, best heard with the diaphragm of the stethoscope, and is usually loudest at the third space on the left border of the sternum with the patient in the upright position, leaning forward, and after deep expiration. The severity of cardiac findings in the acute episode is variable, going from subclinical lesions to severe presentation with fulminating evolution ( Table 54A-3 ).
| Type | Findings |
|---|---|
| Subclinical carditis | Absence of auscultatory evidence of carditis associated with normal radiographic and electrocardiological examinations, except for the presence of first-degree heart block. Doppler echocardiographical features show mild regurgitation of mitral and/or aortic valves with different characteristics from physiological regurgitation (see Table 54A-4 ). |
| Mild carditis | Rapid sleeping pulse, tachycardia out of proportion to fever, possible decrease in the intensity of the first sound, systolic murmur of mild mitral regurgitation, no cardiac enlargement on chest radiography, possible prolongation of the PR interval in the electrocardiographical examination, mild or mild-moderate mitral insufficiency, isolated or associated with mild aortic regurgitation and normal chamber size on echocardiography. |
| Moderate carditis | Clinical signs are more evident than for mild carditis with persistent tachycardia and a more intense murmur of mitral regurgitation, but without thrill, coming as an isolated lesion or associated with aortic diastolic murmur. The mitral regurgitation can be accompanied by a Carey-Coombs murmur, besides findings of incipient heart failure; a mild or mild-moderate degree of cardiac enlargement in the chest radiography due to left-sided chamber hypertrophy and, if present, the pulmonary congestion is discreet; premature beats, ST segment and T wave changes, low voltage, prolongation of QTc or PR intervals may be observed on the electrocardiogram; mild-moderate mitral regurgitation, isolated or associated with aortic valve incompetence of mild or moderate degree, mild-moderate enlargement of the left-side chambers are seen on echocardiography. |
| Severe carditis | In addition to the findings of moderate carditis, symptoms and signs of congestive heart failure are found; valvitis is expressed by murmurs related to more severe degrees of mitral and/or aortic regurgitation and can be associated with pericarditis and arrhythmias. There is evident cardiomegaly with prominent vascular markings on chest radiography; a more severe degree of the electrocardiographic changes of left ventricular hypertrophy is sometimes associated with right ventricular hypertrophy. Moderate-severe or severe mitral and/or aortic insufficiency are observed on echocardiography, and the left cardiac chambers show at least moderate enlargement. |
∗ According to the protocol of the Rheumatic Fever Clinic, Department of Paediatrics, Division of Paediatric Cardiology, Hospital das Clínicas/Federal University of Minas Gerais, Brazil.
Subclinical Valvitis
Until the advent of Doppler echocardiography, the diagnosis of rheumatic valvitis had been exclusively based on the presence of auscultatory findings, supported by radiographic and electrocardiographic abnormalities. By the late 1980s, it proved possible positively to identify subclinical valvitis. 86–89 Such silent carditis is found in patients with isolated arthritis and/or pure chorea, without auscultatory findings of valvar dysfunction, but with a pathological pattern of valvar regurgitation revealed by Doppler echocardiographic interrogation ( Table 54A-4 ). Thickening of the valvar leaflets has also been described. 90,91 Subsequently, regurgitant jets have been observed, with a wide range of prevalence. 57,88,92–96 As trivial leaks of pulmonary, tricuspid, and mitral valves are commonly identified by Doppler echocardiographic investigation in normal subjects at all ages, it is essential to use strict criterions to differentiate pathological from physiological regurgitation (see Table 54A-4 ). Physiological insufficiency can be detected in up to nine-tenths of the normal population, being more frequent in adults than children. 90,97–101 Aortic leaks, however, have rarely been considered physiologic. Mild degrees of mitral and/or aortic regurgitation are most commonly described in rheumatic subclinical valvitis, albeit that mild to moderate degrees have also been identified, mostly involving the aortic valve. 90,102–104 Caution is required when interpreting the evidence of valvar incompetence. Besides the characteristics of the regurgitant jet, it is important to note that the echocardiographic findings do not define the aetiology of the process. They must be considered in the context of the disease, considering associations with other clinical and laboratory manifestations. Although the role of Doppler interrogation has long been recognised, its use without auscultatory support is still controversial. 85,94,105–110 In the last revision of the guidelines for the diagnosis of rheumatic fever by the American Heart Association, in 2002, 22 it was concluded that the existing data was insufficient to include Doppler echocardiographic findings in the absence of clinical manifestations as a criterion for the diagnosis of carditis.
| Type | Criterions |
|---|---|
| Mitral regurgitation ∗ |
|
| Aortic regurgitation ∗ |
|
∗ Thickening of valvar leaflets is an additional finding to support the diagnosis. 90,91
In some patients without auscultatory findings in the early stage of the disease, the murmurs can be identified later. 90,103 Patients, therefore, require serial clinical evaluation, aimed at detecting late clinical evidence of carditis. As mild valvar dysfunctions are most frequently seen in subclinical valvitis, favourable outcomes are expected for the great majority of patients, with anticipated spontaneous healing of the valvar lesions without sequels. 104,110–113 More recent investigations, nonetheless, have demonstrated that the subclinical valvitis can persist for prolonged periods. 90,102,104,110,114 The valvar lesions can remain subclinical in the chronic phase, characterizing subclinical chronic rheumatic heart disease. 45,105,115 Considering the propensity of recurrences to mimic clinical manifestations of the first episode, the increased risk of more severe involvement of the heart must be borne in mind should there be subsequent attacks. 114
Recurrent Carditis
Carditis is rarely present for the first time in recurrences. The term mimetic carditis was proposed, considering the heart almost always to be involved in the subsequent attacks in patients exhibiting carditis in the primary episode. 6,52 The diagnosis of recurrent carditis in patients with an established rheumatic valvar disease is often difficult. The clinical presentation includes changes in the character of the murmur, reappearance of a previous murmur, or detection of a new one as the result of the involvement of an additional valve. In addition, detection of a pericardial friction rub or effusion, and a significant increase in the size of the heart, may also be present. Congestive failure is more common in recurrent carditis. Although the heart is invariably involved in recurrences of patients suffering carditis in the first attack, cardiac failure in the chronic phase could also reflect mechanical stress due to valvar dysfunction, being related to the extent of haemodynamic effects. The epidemiological and clinical context, as well as the evidence of a recent streptococcal infection, therefore, must be considered in the diagnosis of recurrent carditis.
Polyarthritis
Polyarthritis is the most frequent major manifestation seen in older children, adolescents, and adults, but constitutes the least specific clinical finding of rheumatic fever. Its frequency increases with age, being seen in up to three-quarters of patients as an isolated presentation, or in association with other manifestations of the disease. 1 The articular involvement usually occurs early in the illness, with duration and severity greater in adults than in children. Polyarthritis is rarely simultaneous with active chorea, the severity of the articular symptoms and signs being inversely proportional to the degree of carditis. 6,44 Polyarthritis is non-suppurative, asymmetrical, migratory, and self-limited, and does not result in permanent deformity. The classical migratory pattern refers to the sequential involvement of joints. While the process is resolving in one joint, another becomes involved, resulting in an overlapping in time with the participation of more than one joint. There is a marked preference to involve the peripheral large joints, and mainly of the legs. Less frequently, the shoulders, hips, spine, and the small joints of the hands and feet are affected. Tenderness and severe pain, out of proportion to the findings of the physical examination, are the most prominent features, and very prompt relief of the symptoms and signs follows the use of anti-inflammatory agents. The pain occurs in both active and passive movements, is usually diffuse, can show radiation to periarticular areas, and is associated with limitation of motion. Other characteristics of inflammation, such as heat, redness, and swelling, although present, are usually less marked. If untreated, the inflammatory findings last from 1 to 5 days in each joint, reach the higher intensity in the first 2 days, with the entire process subsiding over 2 to 4 weeks. 44
Atypical presentations of arthritis, such as monoarthritis and additive and symmetrical polyarthritis, besides simultaneous participation of several joints, and the longer duration of the inflammatory process, have been described. Involvement of only one joint is often observed if the anti-inflammatory therapy is administered before the migratory characteristic has been established. Jaccoud’s arthritis is considered a rare sequel of recurrent attacks of rheumatic fever, and is a possible exception for residual articular deformity. In this situation, periarticular fibrosis of the metacarpophalangeal joint results in marked ulnar deviation and hyperextension of the proximal interphalangeal joints. 116,117 Post-streptococcal reactive arthritis is related as an acute and non-suppurative arthritic condition following a documented group A streptococcal infection. Its characteristics are not typical of rheumatic fever, and do not meet the Jones criterions. There is a latent period, usually shorter than 10 days, and persistence of mono- or polyarthritis for several months with atypical presentation. Clinical findings include an additive and symmetrical rather a migratory pattern and involvement of small and axial joints, besides a poor response to anti-inflammatory therapy. 118,119 An association with mitral valvar dysfunction has been registered in one-twentieth of the patients. 120 Doubts remain whether post-streptococcal reactive arthritis is a different condition from rheumatic fever, or if the two entities represent diverse expressions of the same disease.
Sydenham’s Chorea
Sydenham’s chorea, chorea minor, or St. Vitus’s dance, affects children and adolescents, more frequently females. It is uncommon after puberty, and is rarely seen in postpuberal males. 121 It has been reported in up to one-third of patients, with a peak incidence at around 8 to 9 years of age. 5,122 The latent period after infection is longer than for arthritis and carditis, varying from 1 to 7 months. It may occur as an isolated manifestation, the so-called pure chorea, or less frequently in association with carditis or arthritis. 26 As a late manifestation, the disorder is rarely associated with arthritis, but may co-exist with clinical or subclinical valvitis in up to two-fifths of patients. 1,45,123,124 Chronic rheumatic heart disease has been described in around one-quarter of patients 20 years after the presentation of isolated chorea. 125
Sydenham’s chorea is usually a self-limited disorder, and diagnosis is based exclusively on clinical examination. It is a manifestation of the central nervous system characterised by muscular weakness, hypotonia, and emotional instability, besides involuntary and purposeless but conscious movements of the skeletal muscles. Although the face and the arms and legs are more often involved, any voluntary muscle may be affected. The presentation of facial grimacing is frequent, besides abrupt but not repetitive movements of the limbs, mainly the hands. The uncoordinated movements are mostly evident when the patient is awake, particularly under stress, excitement, or effort. Oculomotor problems have also been reported, which go into remission in most patients after the improvement of the choreiform movements. 126
The onset is insidious, so that chorea as the first and sole manifestation of rheumatic fever may not be recognised in the early phase, the signs being attributed to behavioural or emotional problems. The child shows attention deficit and inappropriate behaviour, and becomes irritable, restless, and clumsy. Fine muscular incoordination is noted, and voluntary movements, such as unbuttoning clothes or tying shoes laces are difficult to execute. The manifestations become progressively more evident, with disturbances in the speech and handwriting. The signs of muscular weakness and choreiform movements are mostly generalised, sometimes asymmetrical, but one-fifth of patients have hemichorea, with the manifestations limited to one side of the body. So-called chorea paralytica is an expression of generalised and severe presentation, albeit very rare. 122 Certain manoeuvres are helpful to bring out the choreiform movements. When the patient is asked to extend the arms forward, the hands assume the shape of a spoon or dish as a result of wrist flexion and hyperextension of the fingers. The milking sign is demonstrated by alternating increase and decrease in tension when the patient grips the examiner’s hand. If the arms are raised above the head, the hands are involuntarily turned outwards. Undulating movements can be observed when the tongue is protruded, resembling a bag of worms. 5,6,44
Recurrent chorea is not uncommon. More recently, it has been questioned whether all recurrent choreiform episodes are due to rheumatic fever. 127 The severity and the course of the illness up to its resolution are variable. In mild cases, the choreiform movements may subside in few weeks, but most frequently the recovery takes up to 6 months, albeit that in severe cases the manifestation may persist up to more than 2 years. 1 Behavioural abnormalities occur in up to one-third of patients. 128–130 More recently, a broad spectrum of post-streptococcal movement conditions associated with emotional and behaviour disorders have been identified using the acronym PANDAS—paediatric autoimmune neuropsychiatric disorders associated with Streptococcus 131–134
Subcutaneous Nodules
Other than being useful for diagnosis, subcutaneous nodules have a limited value due to their lower frequency. They are one of the most characteristic major criterions, almost invariably associated with severe carditis. 78,135,136 Seen in only one-tenth of patients, their frequency seems to have been reduced over the last decades. 137 On many occasions, the subcutaneous nodules are not noted by the patients. Sometimes they are found only following careful investigation. They usually appear several weeks after the onset of the acute episode, persist from days to weeks, and rarely last longer than 1 month. They can be seen early in recurrences. The nodules are small, varying in size from millimetres to 2 centimetres, and are firm, painless, and freely movable under the skin. They are encountered in clusters, on the extensor surface of the joints and overlying bone prominences, mainly in the large joints of limbs, knuckles, scalp, and along the spine in the paravertebral areas ( Figs. 54A-10 through 54A-12 ).
