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  • Review Article
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Macrophage activation syndrome in the era of biologic therapy

Key Points

  • A 'cytokine storm' is the final pathophysiological pathway in macrophage activation syndrome (MAS), and blocking various cytokines could be an attractive therapeutic strategy

  • Standard doses of anti-IL-1 and anti-IL-6 biologic therapies do not have a major effect on MAS rates even if the underlying disease responds well to the treatment

  • Several case reports suggest that anakinra might be effective at least in some patients with systemic juvenile idiophatic arthritis (sJIA)-associated MAS, particularly when used in high doses

  • Findings from several studies support IFN-γ blockade as a novel therapy for haemophagocytic lymphohistiocytosis (HLH); increasing evidence suggests the same approach could be beneficial in MAS presenting as a complication of rheumatic diseases

  • The exact mechanism of predisposition to MAS in sIJA is yet to be defined, but might be independent of underlying sJIA activity and similar to infection-associated secondary HLH

  • Whole-exome/genome sequencing approaches exploring hypomorphic mutations that affect the cytolytic pathway to support this theory might reveal promising therapeutic alternatives

Abstract

Macrophage activation syndrome (MAS) refers to acute overwhelming inflammation caused by a 'cytokine storm'. Although increasingly recognized as a life-threatening complication of various rheumatic diseases, clinically, MAS is strikingly similar to primary and secondary forms of haemophagocytic lymphohistiocytosis (HLH). Not surprisingly, many rheumatologists prefer the term secondary HLH rather than MAS to describe this condition, and efforts to change the nomenclature are in progress. The pathophysiology of MAS remains elusive, but observations in animal models, as well as data on the effects of new anticytokine therapies on rates and clinical presentations of MAS in patients with systemic juvenile idiopathic arthritis (sJIA), provide clues to the understanding of this perplexing clinical phenomenon. In this Review, we explore the latest available evidence and discuss potential diagnostic challenges in the era of increasing use of biologic therapies.

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Figure 1: Activated macrophages in bone marrow inflammatory infiltrate in MAS.
Figure 2: T cells in bone marrow inflammatory infiltrate in MAS.
Figure 3: Multi-layer model of pathogenic events leading to the development of MAS in the context of rheumatic diseases.

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Acknowledgements

A.A.G. is supported by NIH grants NIAMS R01-AR059049 and NIH P01-AR048929.

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A.A.G. contributed to researching data, discussions of content and writing of the article. A.C.H. contributed to discussions of content, review and editing of the manuscript before submission. F.D.B. contributed to discussions of content, review and editing of the manuscript before submission.

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Correspondence to Alexei A. Grom.

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A.A.G declares that he has served as a consultant and speaker for Novartis and Roche and worked in collaboration with NovImmune. F.D.B declares that he has received unrestricted research grants from Pfizer, AbbVie, Novartis, NovImmune, Roche, and SOBI, and travel support from Roche. A.C.H. declares no competing interests.

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Grom, A., Horne, A. & De Benedetti, F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol 12, 259–268 (2016). https://doi.org/10.1038/nrrheum.2015.179

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