Journal Article

Macrophage activation syndrome in the era of biologic therapy

Grom, Alexei A., Horne, AnnaCarin, De Benedetti, Fabrizio

2016

Overview

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 Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic disease, most notably systemic juvenile idiopathic arthritis. Findings from studies in animal models and from clinical observations, particularly in relation to the effects of anticytokine biologic therapies, have led to new concepts of the pathophysiology of this phenomenon. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/420/2780 / 692/699/1670/427/1304 / Analysis / Animal models / Animals / Antibodies, Monoclonal - therapeutic use / Antibodies, Monoclonal, Humanized - therapeutic use / Antirheumatic Agents - therapeutic use / Apoptosis / Arthritis / Arthritis, Juvenile - drug therapy / Arthritis, Juvenile - immunology / Biological Products - therapeutic use / Care and treatment / Case reports / Cell activation / Cytokine storm / Cytokines / Disease Models, Animal / Genomes / Health aspects / Humans / Inflammation / Interferon-gamma - immunology / Interleukin 1 / Interleukin 1 receptor antagonist / Interleukin 1 Receptor Antagonist Protein - therapeutic use / Interleukin 6 / Interleukin-18 - immunology / Interleukin-1beta - immunology / Interleukin-6 - immunology / Lymphocytes / Lymphohistiocytosis, Hemophagocytic - drug therapy / Lymphohistiocytosis, Hemophagocytic - immunology / Macrophage Activation Syndrome - drug therapy / Macrophage Activation Syndrome - immunology / Macrophages / Medicine & Public Health / Mutation / Pathophysiology / Pediatrics / Recombinant Fusion Proteins - therapeutic use / review-article / Rheumatic diseases / Rheumatology / γ-Interferon