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Macrophage activation syndrome — Clinical Guidelines

Overview

Macrophage activation syndrome (MAS) is a severe, potentially life-threatening hyperinflammatory condition characterized by excessive activation of macrophages and T-lymphocytes, often complicating immunologic and rheumatic disorders 4 5.

Diagnosis

Clinical features include persistent fever, hepatosplenomegaly, cytopenias, and organ dysfunction 4.

Laboratory findings typically show elevated ferritin, triglycerides, and inflammatory markers (e.g., IL-6, TNF-α) 4 8.

Bone marrow aspiration may reveal hemophagocytosis 4 8.

Genetic testing may be considered in primary hemophagocytic lymphohistiocytosis (HLH) 8.

Management

First-line treatment: High-dose corticosteroids (e.g., pulse steroids) 1.

Adjunctive therapies: Intravenous immunoglobulin (IVIG) 1, cyclosporine A 1 5, and anti-TNF agents (e.g., infliximab) 1.

Second-line options: Etoposide in refractory cases 1.

Supportive care: Intensive care monitoring, management of organ failure, and transfusion support 4 5.

Special Populations

Pediatrics: MAS is particularly severe in children, requiring prompt recognition and aggressive management 4.

Comorbidities: Management may need adjustment in patients with underlying autoimmune or rheumatic diseases 4 5.

Key Recommendations

Initiate high-dose corticosteroids as first-line therapy for MAS (Evidence: Strong 1).

Consider adjunctive therapy with IVIG and cyclosporine A in refractory cases (Evidence: Moderate 1).

Early recognition and aggressive supportive care are crucial for improving outcomes in pediatric patients (Evidence: Expert opinion 4).

References

1 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. Rheumatology (Oxford, England) 2025. link 2 Hou C, Zhang XR, Wei J, Wang JN, Gao J, Wang ZJ et al.. METTL1-mediated m. Science immunology 2025. link 3 Shekhar AC, Blumen IJ. Full Moons and Helicopter Emergency Medical Services (HEMS) Activations in The United States. Air medical journal 2023. link 4 Alongi A, Naddei R, De Miglio L, Natoli V, Ravelli A. Macrophage activation syndrome in pediatrics. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 2020. link 5 Saviano A, Petrucci M, Tilli P, Pignataro G, Petruzziello C, Giuliano G et al.. Unexpected macrophage activation syndrome in a healthy young woman: a case report. European review for medical and pharmacological sciences 2020. link 6 Randolph GJ. Macrophages in Marseille. Immunity 2013. link 7 Nathan C. Secretory products of macrophages: twenty-five years on. The Journal of clinical investigation 2012. link 8 Billiau AD, Roskams T, Van Damme-Lombaerts R, Matthys P, Wouters C. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood 2005. link 9 Muta T, Yamano Y. Fulminant hemophagocytic syndrome with a high interferon gamma level diagnosed as macrophage activation syndrome. International journal of hematology 2004. link 10 Steinman RM, Moberg CL. Zanvil Alexander Cohn 1926-1993. The Journal of experimental medicine 1994. link 11 Ohkuma Y, Komano H, Natori S. Identification and characterization of Sarcophaga lectin receptor on the surface of murine macrophages by use of monoclonal antibodies. Journal of biochemistry 1988. link 12 Tschopp J, Masson D, Schäfer S, Peitsch M, Preissner KT. The heparin binding domain of S-protein/vitronectin binds to complement components C7, C8, and C9 and perforin from cytolytic T-cells and inhibits their lytic activities. Biochemistry 1988. link 13 Pho DB, Desbruyères E, Der Terrossian E, Olomucki A. Cytoskeletons of ADP- and thrombin-stimulated blood platelets. Presence of a caldesmon-like protein, alpha-actinin and gelsolin at different steps of the stimulation. FEBS letters 1986. link80660-3) 14 Pacaud M. Separation and identification of the major constituents of cytoplasmic gels from macrophages. European journal of biochemistry 1986. link 15 Reboul A, Prandini MH, Bensa JC, Colomb MG. Characterization of C1q, C1s and C-1 Inh synthesized by stimulated human monocytes in vitro. FEBS letters 1985. link80428-2) 16 Kolb WP, Muller-Eberhard HJ. The membrane attack mechanism of complement. Isolation and subunit composition of the C5b-9 complex. The Journal of experimental medicine 1975. link 17 Kolb WP, Haxby JA, Arroyave CM, Müller-Eberhard HJ. Molecular analysis of the membrane attack mechanism of complement. The Journal of experimental medicine 1972. link

Macrophage activation syndrome