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Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Abstract

Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30–40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro- and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

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Acknowledgements

We thank the members of the International Macrophage Activation Syndrome Study Group for their expertise, collegiality and research efforts. We are also indebted to sJIA and MAS patients and their families for their willing participation in research and acceptance of novel life-sparing therapies. Dr Grom was supported in part by an NIH/NIAMS grant (R01AR059049), Dr Behrens was supported by an Arthritis Foundation Innovative Research Grant and Dr Cron was supported in part by the Arthritis Foundation, Alabama Chapter Endowed Chair in Pediatric Rheumatology.

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Drs Cron and Behrens who serve as consultants to Genentech for the use of Actemra (tocilizumab) to treat sJIA. Dr Cron also serves as a consultant to Novartis on the use of canakinumab to treat sJIA. Other authors declare no conflicts of interest.

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Ravelli, A., Grom, A., Behrens, E. et al. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun 13, 289–298 (2012). https://doi.org/10.1038/gene.2012.3

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