Macrophage activation syndrome: advances towards understanding pathogenesis

Macrophage activation syndrome (MAS), a major cause of morbidity and mortality in pediatric rheumatology, is most strongly associated with systemic juvenile idiopathic arthritis (SJIA). There are no validated diagnostic criteria and early diagnosis is difficult. This review summarizes the progress in understanding of MAS pathophysiology that may help define specific diagnostic biomarkers.

MAS is similar to the autosomal recessive disorders collectively known as familial hemophagocytic lymphohistiocytosis (FHLH), all associated with various genetic defects affecting the cytolytic pathway. Cytolytic function is profoundly depressed in SJIA with MAS as well. This immunologic abnormality distinguishes SJIA from other rheumatic diseases and is caused by both genetic and acquired factors. Phenotypic characterization of hemophagocytic macrophages has been another focus of research. These macrophages express CD163, a scavenger receptor that binds hemoglobin-haptoglobin complexes, and initiate pathways important for adaptation to oxidative stress induced by free iron. Expansion of these macrophages is seen in more than 30% of SJIA patients perhaps representing early stages of MAS. Recent gene expression studies linked expansion of these macrophages to distinct signatures.

Recent advances in understanding of pathophysiologic conditions that favor expansion of hemophagocytic macrophages provide a source of new MAS biomarkers with applicability to clinical practice.