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Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions

Nature Reviews Rheumatology volume 7, pages 416–426 (2011)Cite this article

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Abstract

Systemic juvenile idiopathic arthritis (sJIA) has long been recognized as unique among childhood arthritides, because of its distinctive clinical and epidemiological features, including an association with macrophage activation syndrome. Here, we summarize research into sJIA pathogenesis. The triggers of disease are unknown, although infections are suspects. Once initiated, sJIA seems to be driven by innate proinflammatory cytokines. Endogenous Toll-like receptor ligands, including S100 proteins, probably synergize with cytokines to perpetuate inflammation. These and other findings support the hypothesis that sJIA is an autoinflammatory condition. Indeed, IL-1 is implicated as a pivotal cytokine, but the source of excess IL-1 activity remains obscure and the role of IL-1 in chronic arthritis is less clear. Another hypothesis is that a form of hemophagocytic lymphohistiocytosis underlies sJIA, with varying degrees of its expression across the spectrum of disease. Alternatively, sJIA with MAS might be a genetically distinct subtype. Yet another hypothesis proposes that inadequate downregulation of immune activation is central to sJIA, supporting evidence for which includes 'alternative activation' of monocyte and macrophages and possible deficiencies in IL-10 and T regulatory cells. Some altered immune phenotypes persist during clinically inactive disease, which suggests that this stage might represent compensated inflammation. Despite much progress being made, many questions remain, providing fertile ground for future research.

Key Points

  • The contribution of innate immunity to systemic juvenile idiopathic arthritis (sJIA) is prominent, supporting the classification of sJIA as an autoinflammatory disorder

  • Available data suggest that sJIA is a multigenic disease, and that sJIA with macrophage activation syndrome (MAS) could represent a genetically distinct disease subtype

  • IL-1β is a critical proinflammatory cytokine in early sJIA, whereas arthritis in chronic persistent sJIA is possibly driven by other mediators

  • During active disease, mediators of both inflammatory and anti-inflammatory pathways are detected; among the latter are monocyte/macrophages with features of 'alternative activation'

  • It is possible that clinically inactive disease (with no medication) represents a state of compensated inflammation rather than the absence of immune activity

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Figure 1: Perpetuation of innate immune responses in sJIA.
Figure 2: Secretion of IL-1β by monocytes in inflammatory diseases.
Figure 3: A possible positive feedback cycle involving IL-1β and S100 proteins contributes to perpetuation of chronic inflammation in sJIA.

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Acknowledgements

C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

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Authors and Affiliations

  1. Department of Pediatrics, Stanford University, 300 Pasteur Drive, Stanford, 94305, CA, USA

    Elizabeth D. Mellins & Claudia Macaubas

  2. Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, 333 Burnet Avenue, Cincinnati, 45229-3039, OH, USA

    Alexei A. Grom

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  1. Elizabeth D. Mellins
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  2. Claudia Macaubas
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  3. Alexei A. Grom
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All authors contributed equally to researching data for the article, providing substantial contributions to discussions of content and writing the article. E. D. Mellins reviewed and edited the manuscript before submission.

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Correspondence to Elizabeth D. Mellins.

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Competing interests

E. D. Mellins has acted as a consultant for Genentech, and A. A. Grom has acted as a consultant for Novartis. C. Macaubas, the journal Chief Editor J. Buckland and the CME questions author C. P. Vega declare no competing interests.

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Mellins, E., Macaubas, C. & Grom, A. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol 7, 416–426 (2011). https://doi.org/10.1038/nrrheum.2011.68

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