What is the pathophysiology of acute rheumatic fever (ARF)?

Updated: Dec 10, 2020
  • Author: Robert J Meador, Jr, MD; Chief Editor: Herbert S Diamond, MD  more...
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Although the inciting bacterial agent is well known, susceptibility factors remain unclear. The location of the streptococcal infection seems to play an important role. The clinical syndrome typically follows a streptococcal pharyngitis, but streptococcal cellulitis has never been implicated.

The earliest and most common feature is a painful migratory arthritis, which is present in approximately 80% of patients. Large joints such as knees, ankles, elbows, or shoulders are typically affected. Sydenham chorea was once a common late-onset clinical manifestation but is now rare. [4] Carditis (with progressive congestive heart failure, a new murmur, or pericarditis) may be the presenting sign of unrecognized past episodes and is the most lethal manifestation.

Genetics may contribute, as evidenced by an increase in family incidence. No significant association with class-I human leukocyte antigens (HLAs) has been found, but an increase in class-II HLA antigens DR2 and DR4 has been found in black and white patients, respectively. [5] Evidence suggests that elevated immune-complex levels in blood samples from patients with ARF are associated with HLA-B5. [6]

A meta-analysis of 13 studies suggested that carriage of the HLA-DRB1*07 allele increases susceptibility to ARF/rheumatic heart disease, while carriage of the HLA-DRB1*15 allele protects against it. The frequency of the HLA-DRB1*07 allele was significantly higher in patients compared with controls (odds ratio [OR] = 1.68, P < 0.0001), and the frequency of the HLA-DRB1*15 allele was significantly lower (OR = 0.60, P = 0.03). [7]

Meta-analyses of candidate gene studies suggest that theTGF-β1 [rs1800469] and IL-1β [rs2853550] single-nucleotide polymorphisms contribute to susceptibility to rheumatic heart disease. [8]

In a study of 15 patients with rheumatic heart disease and a control group of 10 patients who had been exposed to group A streptococci but did not develop either acute rheumatic fever or rheumatic heart disease, 13 genes were differentially expressed in the same direction (predominantly decreased) between the two groups. Seven of those were immune response genes involved in cytotoxicity, chemotaxis, and apoptosis. The researchers concluded that the high proportion of differentially expressed apoptotic and immune response genes supports a model of autoimmune and cytokine dysregulation in ARF. [9]

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