Cytokine imbalance in acute rheumatic fever and rheumatic heart disease: Mechanisms and therapeutic implications

Autoimmun Rev. 2022 Dec;21(12):103209. doi: 10.1016/j.autrev.2022.103209. Epub 2022 Oct 11.


Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD) are autoimmune sequelae of Group A Streptococcus infection with significant global disease burden. The pathogenesis of these diseases is poorly understood, and no immune modulating therapies are available to stop progression from ARF to RHD. Cytokines and chemokines are immune signaling molecules critical to the development of autoimmune diseases. An increasing number of studies point to a central role for pro-inflammatory cytokines and chemokines in ARF and RHD pathogenesis, in particular IL-6, IL-8/CXCL8, and TNFα, which are elevated in circulation in both ARF and RHD patients. Histological studies of RHD valve tissue implicates Th1 and Th17 associated pro-inflammatory cytokines, chemokine CXCL9, and the fibrosis-associated cytokine TGF-β in progressive cycles of inflammatory damage and fibrotic repair. Taken together, this suggests immune molecules contribute to both the acute inflammatory disease stage of ARF, as well as cardiac remodeling and valve dysfunction in RHD. Monoclonal antibody blockade of pro-inflammatory cytokines IL-6 and TNFα are approved therapies for many autoimmune diseases and the most successful immunomodulating therapies for rheumatoid arthritis. Current evidence suggests possible benefit for ARF patients from IL-6 and TNFα blockade, in particular to interrupt progression to RHD, and warrants immediate investigation.

Keywords: Acute rheumatic fever; Autoimmunity; Cytokine; Cytokine blockade; Rheumatic heart disease.

Publication types

  • Review

MeSH terms

  • Autoimmune Diseases* / complications
  • Cytokines
  • Humans
  • Interleukin-6
  • Rheumatic Fever* / complications
  • Rheumatic Heart Disease* / etiology
  • Rheumatic Heart Disease* / therapy


  • Cytokines
  • Interleukin-6