Macrophage activation syndrome in the era of biologic therapy

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.

Figure 1. Activated macrophages in bone marrow inflammatory infiltrate in MAS

a | Myelocyte within an activated macrophage. In addition, there are multiple adherent red blood cell and myeloid precursors. b | Activated macrophage engulfing a band neutrophil. c | Band neutrophil and metamyelocyte within an activated macrophage. Nuclei of neutrophil band appear condensed. d | Activated macrophage with haemosiderin deposits and a degenerating phagocytosed nucleated cell. H&E stain, original magnification ×1000. MAS, macrophage activation syndrome. Reproduced with permission from Prahalad, S. et al. Etanercept in the treatment of macrophage activation syndrome. J. Rheumatol. 28, 2120–2124 (2001). All rights reserved.

Figure 2. T cells in bone marrow inflammatory infiltrate in MAS

Immunohistochemical assessment of the T lymphocyte infiltrate in a bone marrow biopsy from a patient with macrophage activation syndrome (MAS) presenting as a complication of systemic juvenile idiopathic arthritis (sJIA). a | Immunohistochemical staining with anti-CD8 antibodies shows numerous CD8⁺ T lymphocytes; b | CD4 staining shows only rare CD4⁺ T lymphocytes.

Figure 3. Multi-layer model of pathogenic events leading to the development of MAS in the context of rheumatic diseases

Genetic factors and the inflammatory milieu created by the underlying rheumatic disease act synergistically to reach the threshold for macrophage activation syndrome (MAS) in the presence of an infectious trigger.