The Big Bad Wolf: Macrophage Activation Syndrome in Childhood-Onset Systemic Lupus Erythematosus

For decades, rheumatologists have recognized that certain patients are at risk for developing life-threatening episodes of systemic hyperinflammation and multiorgan system dysfunction, which was termed macrophage activation syndrome ( MAS ), due to the distinctive finding of highly activated macrophages or histiocytes with hemophagocytic activity seen in tissue.1-3 This clinical picture, including hyperferritinemia; anemia and consumptive coagulopathy; and hepatic, neurologic, and hematologic dysfunction, was proposed by Grom and Passo as well as Ramanan and Baildam to represent a form of secondary hemophagocytic lymphohistiocytosis (HLH).4,5 Primary HLH consists of several rare recessive disorders, typically presenting in childhood, that collectively represent defects in the perforin cytolytic pathway and lead to profound immune dysregulation.6 Interestingly, several studies have shown that children and adults with MAS occurring in the setting of the Stills spectrum disorders—systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD)—have a high prevalence of single copy, hypomorphic mutations in the genes encoding perforin ( PRF1 ) or other key proteins in the cytolytic pathway.7-9 While the most common rheumatic condition associated with MAS in pediatric rheumatology is sJIA, MAS is increasingly recognized as complicating childhood-onset systemic lupus erythematosus (cSLE). However, the mechanisms of MAS specific to patients with cSLE are largely undefined, and whether similar genetic risks are present in these patients has not been carefully examined. In this issue of The Journal of Rheumatology ,10 Lahiry and colleagues describe the prevelance of HLH-related gene variants found in a large, single-center cohort of cSLE. The authors identified 19 patients in the lupus cohort at The Hospital for Sick Children in Toronto (SickKids) who had been diagnosed with MAS and underwent whole-exome sequencing (WES) and/or whole-genome sequencing (WGS). These were compared to 62 patients with cSLE who had WGS performed for suspected monogenic lupus … Address correspondence to Dr. G.S. Schulert, Division of Rheumatology, Cincinnati Children’s Hospital, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45208, USA. Email: Grant.schulert{at}cchmc.org.

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