Makrophagenaktivierungssyndrom: Notfall mit therapeutischen Herausforderungen

Zusammenfassung

Das Makrophagenaktivierungssyndrom (MAS) ist eine gefürchtete potenziell lebensbedrohliche Komplikation rheumatologisch-entzündlicher Erkrankungen. Durch massive Aktivierung und Proliferation von T-Lymphozyten und Makrophagen kommt es beim MAS zu Hyperinflammation und Zytokinsturm unter Beteiligung proinflammatorischer Zytokine. Diese umfassen vor allem IL-1, -6, -18 (IL: Interleukin) und IFN-γ (IFN: Interferon). Labormedizinische Warnzeichen für ein MAS bei systemischer Inflammation sind eine (Thrombo-)Zytopenie, Transaminasenerhöhung und Hyperferritinämie. Auch ein Abfall der Blutsenkungsgeschwindigkeit (BSG) bei hohem C-reaktivem Protein (CRP) und eine Koagulopathie sollten alarmieren. Dabei ist der Trend im Labor mitunter entscheidender als die absoluten Werte. Die Diagnosestellung eines MAS ist herausfordernd; klinische Scores, Klassifikationskriterien und Biomarker (z. B. IL-18, CXCL9 [CXC-Ligand 9] und sIL-2R [löslicher Interleukin-2-Rezeptor]) können bei der Differenzialdiagnose unterstützen. Eine schnelle Diagnosestellung mit effektiver Therapie ist maßgeblich für das Outcome. Therapeutisch sind Hochdosis-Glukokortikoide sowie IL-1- und IFN-γ-Inhibitoren vielversprechend, wobei die Evidenzlage bei nicht mit einem Still-Syndrom assoziierten MAS limitiert bleibt.

Schlüsselwörter

Hyperinflammation - Zytokinsturm-Syndrome - systemische juvenile idiopathische Arthritis/Still-Erkrankung - autoinflammatorische Erkrankungen

Publikationsverlauf

Artikel online veröffentlicht:
01. Dezember 2025

• Literatur

• 1 Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies. Annu Rev Med 2015; 66: 145-159
• 2 Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001; 85: 421-426
• 3 Minoia F, Davi S, Horne A. et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol 2014; 66: 3160-3169
• 4 Ramanan AV, Baildam EM. Macrophage activation syndrome is hemophagocytic lymphohistiocytosis – need for the right terminology.. J Rheumatol 2002; 29: 1105 author reply 1105
• 5 Jordan MB, Allen CE, Greenberg J. et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer 2019; 66: e27929
• 6 Kaufman KM, Linghu B, Szustakowski JD. et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2014; 66: 3486-3495
• 7 Halyabar O, Chang MH, Schoettler ML. et al. Calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Pediatr Rheumatol Online J 2019; 17: 7
• 8 Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol 2016; 12: 259-268
• 9 Behrens EM, Beukelman T, Paessler M. et al. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol 2007; 34: 1133-1138
• 10 Fautrel B, Mitrovic S, De Matteis A. et al. EULAR/PReS recommendations for the diagnosis and management of Still’s disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still’s disease. Ann Rheum Dis 2024; 83: 1614-1627
• 11 De Matteis A, Bindoli S, De Benedetti F. et al. Systemic juvenile idiopathic arthritis and adult-onset Still’s disease are the same disease: evidence from systematic reviews and meta-analyses informing the 2023 EULAR/PReS recommendations for the diagnosis and management of Still’s disease. Ann Rheum Dis 2024; 83: 1748-1761
• 12 Petty RE, Southwood TR, Manners P. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004; 31: 390-392
• 13 Borgia RE, Gerstein M, Levy DM. et al. Features, treatment, and outcomes of macrophage activation syndrome in childhood-onset systemic lupus erythematosus. Arthritis Rheumatol 2018; 70: 616-624
• 14 Poddighe D, Dauyey K. Macrophage activation syndrome in juvenile dermatomyositis: a systematic review. Rheumatol Int 2020; 40: 695-702
• 15 Jeong DC, Lee SY. Macrophage activation syndrome in Kawasaki disease: a literature review of Korean studies. J Rheum Dis 2025; 32: 105-112
• 16 Inguscio G, Romano S, Mastrolia MV. et al. Macrophage activation syndrome in Kawasaki disease: Insights from a systematic literature review on diagnosis, clinical features, and treatment. Children (Basel) 2025; 12: 349
• 17 Chatham WW. Macrophage activation syndrome in the setting of rheumatic diseases. In Cron RQ, Behrens EM. Cytokine Storm Syndrome. Cham: Springer International Publishing; 2019: 423-434
• 18 Gamez-Gonzalez LB, Murata C, Garcia-Silva J. et al. Macrophage activation syndrome in MIS-C. Pediatrics 2024; 154: e2024066780
• 19 Lee J, Bae KS, Rhim JW. et al. Macrophage activation syndrome in children: update on diagnosis and treatment. Children (Basel) 2024; 11: 755
• 20 Grom AA, Ilowite NT, Pascual V. et al. Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab. Arthritis Rheumatol 2016; 68: 218-228
• 21 Ulloa-Gutierrez R, Alphonse MP, Dhanranjani A. et al. Kawasaki disease-associated cytokine storm syndrome. In Cron RQ, Behrens EM. Cytokine Storm Syndrome. Cham: Springer International Publishing; 2019: 393-406
• 22 Holzinger D. MAS in der pädiatrischen Rheumatologie. In Wagner N, Dannecker G, Kallinich T. Hrsg. Pädiatrische Rheumatologie. Berlin, Heidelberg: Springer; 2022: 429-436
• 23 Weiss ES, Girard-Guyonvarc'h C, Holzinger D. et al. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood 2018; 131: 1442-1455
• 24 Minoia F, Bovis F, Davi S. et al. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Ann Rheum Dis 2019; 78: 1357-1362
• 25 Hayden A, Lin M, Park S. et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv 2017; 1: 2529-2534
• 26 Nigrovic PA. Macrophage activation syndrome. Arthritis Rheumatol 2025; 77: 367-379
• 27 Canna SW, de Jesus AA, Gouni S. et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet 2014; 46: 1140-1146
• 28 Ulu K, Aliyev E, Kilic Konte E. et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis on anti-interleukin-1 or –6 therapy. Rheumatology (Oxford) 2024; 63: SI167-SI172
• 29 Henderson LA, Cron RQ. Macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis in childhood inflammatory disorders: diagnosis and management. Paediatr Drugs 2020; 22: 29-44
• 30 Ravelli A, Minoia F, Davi S. et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol 2016; 68: 566-576
• 31 Schulert GS, Minoia F, Bohnsack J. et al. Effect of biologic therapy on clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2018; 70: 409-419
• 32 Baldo F, Erkens RGA, Mizuta M. et al. Current treatment in macrophage activation syndrome worldwide: a systematic literature review to inform the METAPHOR project. Rheumatology (Oxford) 2025; 64: 32-44
• 33 Tristano AG, Casanova-Escalona L, Torres A. et al. Macrophage activation syndrome in a patient with systemic onset rheumatoid arthritis: rescue with intravenous immunoglobulin therapy. J Clin Rheumatol 2003; 9: 253-258
• 34 Chellapandian D, Das R, Zelley K. et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol 2013; 162: 376-382
• 35 Canna S, Frankovich J, Higgins G. et al. Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist. Pediatr Rheumatol Online J 2009; 7: 21
• 36 Naniwa T, Uehara K, Yamabe T. et al. Reintroduction of tocilizumab elicited macrophage activation syndrome in a patient with adult-onset Still’s disease with a previous successful tocilizumab treatment. Mod Rheumatol Case Rep 2021; 5: 360-364
• 37 Yamabe T, Ohmura SI, Uehara K. et al. Macrophage activation syndrome in patients with adult-onset Still’s disease under tocilizumab treatment: A single-center observational study. Mod Rheumatol 2022; 32: 169-176
• 38 Bindoli S, De Matteis A, Mitrovic S. et al. Efficacy and safety of therapies for Still’s disease and macrophage activation syndrome (MAS): a systematic review informing the EULAR/PReS guidelines for the management of Still’s disease. Ann Rheum Dis 2024; 83: 1731-1747
• 39 Horne A, von Bahr Greenwood T, Chiang SCC. et al. Efficacy of moderately dosed etoposide in macrophage activation syndrome-hemophagocytic lymphohistiocytosis. J Rheumatol 2021; 48: 1596-1602
• 40 De Benedetti F, Grom AA, Brogan PA. et al. Efficacy and safety of emapalumab in macrophage activation syndrome. Ann Rheum Dis 2023; 82: 857-865
• 41 Ma Y, Chen X, Wang M. et al. Ruxolitinib targets JAK-STAT signaling to modulate neutrophil activation in refractory macrophage activation syndrome. Blood 2025; 146: 612-627
• 42 Honda M, Moriyama M, Kondo M. et al. Tofacitinib-induced remission in refractory adult-onset Still’s disease complicated by macrophage activation syndrome. Scand J Rheumatol 2020; 49: 336-338