Macrophage Activation Syndrome (MAS) is a severe, potentially life-threatening complication where the immune system becomes overactivated.
Macrophages and T-cells proliferate uncontrollably and release a massive amount of inflammatory cytokines- a cytokine storm.
MAS is a life-threatening acquired form of hemophagocytic lymphohistiocytosis (HLH) that occurs in at least 10% of patients with systemic JIA and can develop at any point in the disease course.
MAS also complicates other autoinflammatory/autoimmune diseases, most notably adult-onset Still’s disease, systemic lupus erythematosus, and Kawasaki disease, and less commonly juvenile dermatomyositis, rheumatoid arthritis, and Sjögren’s syndrome.
Macrophage activation-like syndrome (MALS), occurs in roughly 3–4% of sepsis and is associated with early mortality.
Patients with systemic JIA–associated MAS often have markedly elevated interleukin-18 levels, and interleukin-18–induced interferon-γ production is proposed to play a critical pathogenic role—supported by the effectiveness of interferon-γ inhibitors in treatment.
It falls within the HLH spectrum: primary (familial) HLH results from rare defects in the perforin pathway causing severe inflammation and death in early childhood, whereas acquired HLH can be triggered by infection, cancer, or rheumatic disease flares—when linked to rheumatic disease it is termed MAS.
It is a form of secondary hemophagocytic lymphohistiocytosis (HLH), most often triggered by rheumatologic disease — especially systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease.
Variants in HLH-related genes have been found in up to one third of patients with systemic JIA who develop MAS.
Can also be triggered by infections (especially viral, like EBV), lupus, or other autoimmune conditions.
Typical findings:
Persistent high fever Enlarged liver/spleen Low blood counts (cytopenias) Very high ferritin (often extremely elevated) Abnormal liver enzymes, coagulopathy (low fibrinogen, high D-dimer) Rash, lymph node swelling
Diagnosis:
Based on clinical criteria plus labs (ferritin, triglycerides, fibrinogen, cytopenias) — bone marrow biopsy may show hemophagocytosis.
Key laboratory features are sustained fever, extreme hyperferritinemia, cytopenias (2–3 lineages), a fibrinolytic/DIC-like coagulopathy, hypertriglyceridemia, and liver dysfunction, with hemophagocytosis and CD163+ histiocytes on bone marrow examination.
Elevated soluble CD25 (sIL-2R) and soluble CD163 support the diagnosis.
Ferritin is a useful diagnostic and surrogate marker—in the sepsis/MALS setting, concentrations >4,420 ng/mL were highly specific.
Treatment:
High-dose corticosteroids Cyclosporine Biologics like anakinra (IL-1 blocker) — increasingly used, especially in sJIA-associated MAS Treating the underlying trigger (infection, disease flare) Severe cases may need ICU care
The mainstay remains high-dose parenteral corticosteroids, with cyclosporine for refractory cases.
Anakinra (IL-1 receptor antagonist) has shown dramatic benefit in systemic JIA–associated MAS and is being studied in sepsis-associated MALS.\\
Emerging cytokine-directed options include IFN-γ inhibition (emapalumab), IL-18 blockade, IL-6 receptor blockade, and JAK inhibitors.
Prompt recognition and immediate treatment are essential given the potential for a rapidly fatal course.
Advances in recognition and therapy—including high-dose glucocorticoids, high-dose interleukin-1 inhibitors, and interferon-γ inhibitors—have greatly reduced mortality.
A common hypothesis centers on defective lymphocyte cytolytic activity—the inability of NK cells and cytotoxic CD8 T cells to lyse activated antigen-presenting cells leads to prolonged immune cell interactions and amplification of a proinflammatory cytokine cascade, culminating in a cytokine storm with macrophage activation and hemophagocytosis.
Implicated cytokines include IFN-γ, IL-1, IL-6, IL-18, IL-33, and TNF.
Recent work in Still’s disease–associated MAS also identifies a type I interferon signature and expansion of cycling CD38+HLA-DR+ lymphocytes, with IFN-I acting synergistically with IL-15; JAK inhibition mitigated this response in vitro.