Aetiology

Acute rheumatic fever (ARF) is an autoimmune disease. It is the result of group A streptococcal infection triggering an autoimmune response in a susceptible host.

It is estimated that between 3% and 6% of any population may be susceptible to ARF and this proportion appears to be fairly consistent across different population groups around the world.[1][15] Familial clustering has been reported and twin studies indicate high heritability.[16][17]

Expression of D8/17 antigen has been observed to be associated with ARF in a number of populations, including Australia, Israel, Russia, Mexico, and Chile.[18][19][20] However, this association is not universal and no such association has been found in the US.[21]

Particular ethnic groups appear to be at higher risk of ARF than others. This is particularly evident in high-income countries, where indigenous populations experience dramatically higher rates of ARF compared with their non-indigenous counterparts, including Maori children in New Zealand, Aboriginal children in Australia, and Polynesian children in Hawaii.[22][23][24][25] However, it remains unclear whether these associations are related to environmental factors or an underlying inherited susceptibility.

Genome-wide association studies have identified genetic determinants of susceptibility to rheumatic heart disease, with novel loci identified in studies in Africa, Australia, and Oceania.[26][27][28] Studies are ongoing that may further identify target genes or interventions.

Pathophysiology

Although it is clear that acute rheumatic fever (ARF) is an autoimmune disease, the exact nature of the pathogenesis of ARF is still uncertain.

It has previously been considered that ARF follows group A streptococcal pharyngitis but not pyoderma, although this has long been questioned.[29] Studies now show that group A streptococcus-positive throat or skin swab is strongly associated with subsequent ARF, suggesting that group A streptococcal skin infection can also trigger ARF.[30]

The interaction between group A streptococci and a susceptible host leads to an autoimmune response directed against cardiac, synovial, subcutaneous, epidermal, and neuronal tissues.

It is believed that both cross-reactive antibodies and cross-reactive T cells play a role in the disease. Molecular mimicry between group A Streptococcus pyogenes antigens and human host tissue is thought to be the basis of this cross-reactivity.[31][32] Putative cross-reactive epitopes on S pyogenes include the M-protein and N-acetyl glucosamine. Monoclonal antibodies against these antigens cross-react with cardiac myosin and other alpha-helical cardiac proteins such as laminin, tropomyosin, keratin, and vimentin, as well as proteins in other target organs and tissues such as synovium, neuronal tissue, subcutaneous, and dermal tissues.

It has been proposed that the carditis of ARF is initiated by cross-reactive antibodies that recognise the valve endothelium and laminin.[33] Vascular cell adhesion-molecule-1 is up-regulated at the valve and aids in recruitment and infiltration of these T cells. The T cells initiate a predominantly TH1 response with the release of beta-interferon. Inflammation leads to neovascularisation, which allows further recruitment of T cells. It is believed that epitope spreading may occur in the valve whereby T cells respond against other cardiac tissues such as vimentin and tropomyosin, leading to granulomatous inflammation and the establishment of chronic rheumatic heart disease. Th17 cells (unique T helper cells) also appear to play an important role in the pathogenesis of ARF.[34]

Rheumatic inflammation in the heart may affect the pericardium (often asymptomatic), the myocardium (rarely contributes to cardiac failure), or the endocardium and valvular tissue (the most commonly affected). Rheumatic granulomatous inflammation manifests in the myocardium as Aschoff bodies.[35] These may disrupt cardiac electrical conduction pathways leading to prolongation of the PR interval on electrocardiogram, and occasionally more advanced arrhythmias.

Classification

World Health Organization Expert Consultation: rheumatic fever and rheumatic heart disease, 2004[1]

This commonly used schema classifies rheumatic fever into categories based on whether it is the first episode (primary), whether the patient has had an episode of rheumatic fever previously (recurrent), or whether the patient has established rheumatic heart disease (chronic rheumatic heart disease [RHD]).

  • Primary episode of acute rheumatic fever (ARF): a patient without a prior episode of rheumatic fever and without evidence of established RHD presents with a clinical illness that meets the requirements of the Jones criteria for diagnosis of ARF.

  • Recurrent episode of ARF: a patient who has had documented rheumatic fever in the past, but without evidence of established RHD, who presents with a new clinical illness that meets the requirements of the Jones criteria for diagnosis of ARF.

  • Recurrent episode of ARF in patients with RHD: a patient who has evidence of established RHD, who presents with a new clinical illness that meets the requirements of the Jones criteria for diagnosis of ARF.

Note that the 2015 Jones criteria differ for low-risk and moderate- to high-risk populations. The criteria also allow for diagnosis of possible ARF (i.e., patients, generally in high-incidence settings, in whom the clinician is highly suspicious of the diagnosis of ARF, but who do not quite meet the Jones criteria, perhaps because full testing facilities are not available).[2] See Criteria.

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