Macrophage activation syndrome (MAS) is a form of secondary hemophagocytic lymphohistiocytosis (HLH) that is a complication of autoimmune and autoinflammatory diseases. Clinically, patients present with persistent high-grade fever, cytopenia, striking hyperferritinemia, coagulopathy, transaminitis, hypertriglyceridemia, and haemophagocytosis, that can escalate rapidly to multiorgan failure and carries a high risk of mortality if not promptly recognized. Both primary and secondary HLH including MAS are characterised by uncontrolled activation of macrophages leading to the pathgnomonic histopathological feature -haemophagocytosis.  Central to the immunopathogenesis of HLH is a primary or acquired cytolytic defect of natural killer cells and T cells which leads to ineffective clearance of antigens (infection or autoantigen) and activated immune cells. The persistence of antigens leads to macrophage activation and cytokine storm. The immunopathogenesis of MAS is considered similar although NK cell function is not well studied in MAS.

MAS has been extensively described in systemic juvenile idiopathic arthritis and adult-onset Still’s disease; however, it can occur in systemic lupus erythematosus and dermatomyositis as well.   In most studies active disease itself is found to trigger MAS with infections, drugs and malignancy being occasional triggers. One study in SJIA detected the presence of single copy mutations of genes causing HLH in 40% of patients with SJIA MAS indicating that genetic background may be important.  Early symptoms often mimic active rheumatic disease or severe infection, including high fever, cytopenia, transaminase elevation and hyperferritinaemia, and can vary rapidly between and within patients. Existing diagnostic criteria—such as HLH-04, MAS-2016, and the H-Score—are useful within their original contexts but lack universal sensitivity and specificity. While ferritin remains a sensitive but nonspecific marker, emerging biomarkers targeting T-cell (soluble CD25) and macrophage activation (CD163), inflammasome activity (IL-18) and interferon-gamma pathways offer promising tools for earlier and more precise detection. Addressing these diagnostic limitations is critical, as the earliest stages of HLH/MAS represent the window in which timely intervention can most profoundly influence patient outcomes.

METAPHOR (Macrophage Activation Syndrome and Hemophagocytic Lymphohistiocytosis: Pathogenesis, Outcomes, and Response) was an international collaborative effort aimed at improving understanding of MAS and emphasized early diagnosis and evolving treatment of MAS. The treatment of MAS is rapidly evolving from broad immunosuppression to targeted anti-cytokine treatment. SJIA MAS is typically treated with IL-1 blockade or IL-6 blockade. A recent series has shown efficacy of emapalumab in SJIA MAS. Emapalumab blocks interferon gamma which is key cytokine in HLH /MAS and has shown efficacy in treating primary HLH. Other drugs that are likely to be useful based on biological basis are JAK inhibitors especially ruxolitinib which has been tried successfully in a few patients with MAS. Broad immunosuppression including steroids and cyclosporine continue to be used especially in lupus MAS till more data for targeted treatments emerge.
Macrophage activation syndrome (MAS) remains a formidable challenge in adult rheumatology due to its rapid progression, diagnostic complexity, and limited high-quality evidence guiding treatment. Management still relies heavily on expert opinion, highlighting a critical gap in standardized, evidence-based approaches. Addressing these unmet needs through well-designed studies and consensus-driven guidelines could transform patient outcomes.

References

• Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol2019;10:1–11.
• Baldo F, Erkens RGA, Mizuta M, Rogani G, Lucioni F, Bracaglia C, et al. Current treatment in macrophage activation syndrome worldwide: a systematic literature review to inform the METAPHOR project. Rheumatology2024; 64(1):32-44.
• Benedetti F De, Grom AA, Brogan PA, Bracaglia C, Pardeo M, Marucci G, et al. Efficacy and safety of emapalumab in macrophage activation syndrome. Ann Rheum Dis2023;82:857–865.