Macrophage Activation Syndrome (MAS)

  • Bella Mehta
  • Petros Efthimiou


Macrophage activation syndrome (MAS) is a life-threatening systemic immune-mediated condition and a catastrophic complication of autoinflammatory conditions such as adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA). It is a subtype of hemophagocytic lymphohistiocytosis (HLH) associated with underlying rheumatologic conditions, both autoimmune and autoinflammatory. The patients are often acutely ill from an ongoing “cytokine storm,” and there is significant morbidity and mortality associated with it. Aggressive treatment with high-dose intravenous corticosteroids, immunomodulators, antineoplastic agents, and, depending on the underlying etiology, biologics is necessary to prevent organ damage and improve survival.


Macrophage activation syndrome Reactive hemophagocytosis syndrome Hyperferritinemia Cytopenia Cytokine storm Persistent macrophage activation 


  1. 1.
    Dhote R, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum. 2003;49(5):633–9.CrossRefGoogle Scholar
  2. 2.
    Felix FH, Leal LK, Fontenele JB. Cloak and dagger: the case for adult onset still disease and hemophagocytic lymphohistiocytosis. Rheumatol Int. 2009;29(8):973–4.CrossRefGoogle Scholar
  3. 3.
    Kirino Y, et al. Increased serum HO-1 in hemophagocytic syndrome and adult-onset Still's disease: use in the differential diagnosis of hyperferritinemia. Arthritis Res Ther. 2005;7(3):R616–24.CrossRefGoogle Scholar
  4. 4.
    Wang Z, et al. Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocytic lymphohistiocytosis. Int J Hematol. 2009;90(4):501–5.CrossRefGoogle Scholar
  5. 5.
    Pringe A, et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: an under-recognized complication? Lupus. 2007;16(8):587–92.CrossRefGoogle Scholar
  6. 6.
    Davi S, et al. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2011;38(4):764–8.CrossRefGoogle Scholar
  7. 7.
    Donn R, et al. Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2008;58(3):869–74.CrossRefGoogle Scholar
  8. 8.
    Hazen MM, et al. Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2008;58(2):567–70.CrossRefGoogle Scholar
  9. 9.
    Durand M, et al. Macrophage activation syndrome treated with anakinra. J Rheumatol. 2010;37(4):879–80.CrossRefGoogle Scholar
  10. 10.
    Tristano AG. Macrophage activation syndrome: a frequent but under-diagnosed complication associated with rheumatic diseases. Med Sci Monit. 2008;14(3):RA27–36.PubMedGoogle Scholar
  11. 11.
    Kumakura S, Murakawa Y. Clinical characteristics and treatment outcomes of autoimmune-associated hemophagocytic syndrome in adults. Arthritis Rheumatol. 2014;66(8):2297–307.CrossRefGoogle Scholar
  12. 12.
    Arlet JB, et al. Reactive haemophagocytic syndrome in adult-onset Still's disease: a report of six patients and a review of the literature. Ann Rheum Dis. 2006;65(12):1596–601.CrossRefGoogle Scholar
  13. 13.
    Ravelli A, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr. 2005;146(5):598–604.CrossRefGoogle Scholar
  14. 14.
    Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85(5):421–6.CrossRefGoogle Scholar
  15. 15.
    Zhang K, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794–8.CrossRefGoogle Scholar
  16. 16.
    Meeths M, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood. 2011;118(22):5783–93.CrossRefGoogle Scholar
  17. 17.
    Falini B, et al. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood. 1990;75(2):434–44.PubMedGoogle Scholar
  18. 18.
    Jaffe ES, et al. Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis. Am J Med. 1983;75(5):741–9.CrossRefGoogle Scholar
  19. 19.
    Henter JI, et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78(11):2918–22.PubMedGoogle Scholar
  20. 20.
    Osugi Y, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood. 1997;89(11):4100–3.PubMedGoogle Scholar
  21. 21.
    Takada H, et al. Oversecretion of IL-18 in haemophagocytic lymphohistiocytosis: a novel marker of disease activity. Br J Haematol. 1999;106(1):182–9.CrossRefGoogle Scholar
  22. 22.
    Schneider EM, et al. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood. 2002;100(8):2891–8.CrossRefGoogle Scholar
  23. 23.
    Teruya-Feldstein J, et al. MIP-1alpha expression in tissues from patients with hemophagocytic syndrome. Lab Investig. 1999;79(12):1583–90.PubMedGoogle Scholar
  24. 24.
    George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014;5:69–86.CrossRefGoogle Scholar
  25. 25.
    Behrens EM, et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest. 2011;121(6):2264–77.CrossRefGoogle Scholar
  26. 26.
    Terrell CE, Jordan MB. Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. Blood. 2013;121(26):5184–91.CrossRefGoogle Scholar
  27. 27.
    Mazodier K, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood. 2005;106(10):3483–9.CrossRefGoogle Scholar
  28. 28.
    Ho C, et al. Marrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability. Am J Clin Pathol. 2014;141(1):62–71.CrossRefGoogle Scholar
  29. 29.
    Goel S, Polski JM, Imran H. Sensitivity and specificity of bone marrow hemophagocytosis in hemophagocytic lymphohistiocytosis. Ann Clin Lab Sci. 2012;42(1):21–5.PubMedGoogle Scholar
  30. 30.
    Gupta A, et al. The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;51(3):402–4.CrossRefGoogle Scholar
  31. 31.
    Weaver LK, Behrens EM. Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Curr Opin Rheumatol. 2014;26(5):562–9.CrossRefGoogle Scholar
  32. 32.
    Yokota S, et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis under treatment with tocilizumab. J Rheumatol. 2015;42:712.CrossRefGoogle Scholar
  33. 33.
    Singh S, Samant R, Joshi VR. Adult onset Still’s disease: a study of 14 cases. Clin Rheumatol. 2008;27(1):35–9.CrossRefGoogle Scholar
  34. 34.
    Sumegi J, et al. Gene-expression signatures differ between different clinical forms of familial hemophagocytic lymphohistiocytosis. Blood. 2013;121(7):e14–24.CrossRefGoogle Scholar
  35. 35.
    Henter JI, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.CrossRefGoogle Scholar
  36. 36.
    Stephan JL, et al. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford). 2001;40(11):1285–92.CrossRefGoogle Scholar
  37. 37.
    Allen CE, et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227–35.CrossRefGoogle Scholar
  38. 38.
    Shah NN, et al. Extracavitary primary effusion lymphoma initially presenting with hemophagocytic lymphohistocytosis. Clin Lymphoma Myeloma Leuk. 2014;14(5):e157–60.CrossRefGoogle Scholar
  39. 39.
    Belyea B, et al. Spontaneous resolution of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2010;55(4):754–6.CrossRefGoogle Scholar
  40. 40.
    Imashuku S. Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010. J Pediatr Hematol Oncol. 2011;33(1):35–9.CrossRefGoogle Scholar
  41. 41.
    George TI, et al. Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and review of the literature. Pediatr Blood Cancer. 2005;44(3):270–6.CrossRefGoogle Scholar
  42. 42.
    Fox CP, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults characterized by high viral genome load within circulating natural killer cells. Clin Infect Dis. 2010;51(1):66–9.CrossRefGoogle Scholar
  43. 43.
    Chellapandian D, et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013;162(3):376–82.CrossRefGoogle Scholar
  44. 44.
    Parvaneh N, Filipovich AH, Borkhardt A. Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases. Br J Haematol. 2013;162(5):573–86.CrossRefGoogle Scholar
  45. 45.
    Thoden J, et al. Fatal hemophagocytic syndrome in a patient with a previously well-controlled asymptomatic HIV infection after EBV reactivation. J Infect. 2012;64(1):110–2.CrossRefGoogle Scholar
  46. 46.
    Kelesidis T, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Los Angeles County. J Med Virol. 2012;84(5):777–85.CrossRefGoogle Scholar
  47. 47.
    Tse E, Kwong YL. Epstein Barr virus-associated lymphoproliferative diseases: the virus as a therapeutic target. Exp Mol Med. 2015;47:e136.CrossRefGoogle Scholar
  48. 48.
    Park KH, et al. Acute human immunodeficiency virus syndrome presenting with hemophagocytic lymphohistiocytosis. Yonsei Med J. 2008;49(2):325–8.CrossRefGoogle Scholar
  49. 49.
    Safdar SM, et al. Fatal hemophagocytic syndrome as a manifestation of immune reconstitution syndrome in a patient with acquired immunodeficiency syndrome. Saudi Med J. 2013;34(8):861–4.PubMedGoogle Scholar
  50. 50.
    Yamada M, et al. Unique expression pattern of viral proteins in human herpesvirus 8-positive plasmablastic lymphoma: a case report. Int J Clin Exp Pathol. 2014;7(9):6415–8.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Kaplan LD. Human herpesvirus-8: Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma. Hematology Am Soc Hematol Educ Program. 2013;2013:103–8.CrossRefGoogle Scholar
  52. 52.
    Fernandes F, et al. Simultaneous presentation of Kaposi sarcoma and HHV8-associated large B-cell lymphoma in the same lymph node: a rare diagnosis in an HIV-negative patient. Am J Case Rep. 2013;14:263–6.CrossRefGoogle Scholar
  53. 53.
    Fleischmann RM, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(8):1006–12.CrossRefGoogle Scholar
  54. 54.
    Nigrovic PA, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum. 2011;63(2):545–55.CrossRefGoogle Scholar
  55. 55.
    Zeft A, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol. 2009;15(4):161–4.CrossRefGoogle Scholar
  56. 56.
    Mehta B, Kasturi S, Teruya-Feldstein J, Horwitz S, Bass AR, Erkan D. Adult-Onset Still’s Disease and Macrophage-Activating Syndrome Progressing to Lymphoma: a Clinical Pathology Conference Held by the Division of Rheumatology at Hospital for Special Surgery. HSS J. 2018;14(2):214–21. Epub 2018 Mar 26.CrossRefGoogle Scholar
  57. 57.
    Balwierz W, Czogala M, Czepko E. Anaplastic large cell lymphoma associated with hemophagocytic lymphohistiocytosis: a case report and review of the literature. Przegl Lek. 2010;67(6):436–8.PubMedGoogle Scholar
  58. 58.
    Hagihara M, et al. Lymphocyte-depleted Hodgkin lymphoma complicating hemophagocytic lymphohistiocytosis as an initial manifestation: a case report and review of the literature. Intern Med. 2012;51(21):3067–72.CrossRefGoogle Scholar
  59. 59.
    Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013;2013:605–11.CrossRefGoogle Scholar
  60. 60.
    Kelly A, Ramanan AV. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol. 2008;4(11):615–20.CrossRefGoogle Scholar
  61. 61.
    Bruck N, et al. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol. 2011;17(1):23–7.CrossRefGoogle Scholar
  62. 62.
    De Benedetti F, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–95.CrossRefGoogle Scholar
  63. 63.
    Aeberli D, et al. Inhibition of the TNF-pathway: use of infliximab and etanercept as remission-inducing agents in cases of therapy-resistant chronic inflammatory disorders. Swiss Med Wkly. 2002;132(29–30):414–22.PubMedGoogle Scholar
  64. 64.
    Prahalad S, et al. Etanercept in the treatment of macrophage activation syndrome. J Rheumatol. 2001;28(9):2120–4.PubMedGoogle Scholar
  65. 65.
    Ramanan AV, Schneider R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2003;30(2):401–3.PubMedGoogle Scholar
  66. 66.
    Atteritano M, et al. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. 2012;16(10):1414–24.PubMedGoogle Scholar
  67. 67.
    Stern A, Riley R, Buckley L. Worsening of macrophage activation syndrome in a patient with adult onset Still’s disease after initiation of etanercept therapy. J Clin Rheumatol. 2001;7(4):252–6.CrossRefGoogle Scholar
  68. 68.
    Marsh RA, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60(1):101–9.CrossRefGoogle Scholar
  69. 69.
    Bosman G, et al. The role of rituximab in a case of EBV-related lymphoproliferative disease presenting with haemophagocytosis. Neth J Med. 2009;67(8):364–5.PubMedGoogle Scholar
  70. 70.
    Balamuth NJ, et al. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2007;29(8):569–73.CrossRefGoogle Scholar
  71. 71.
    Sonke GS, et al. Poor outcomes of chronic active Epstein-Barr virus infection and hemophagocytic lymphohistiocytosis in non-Japanese adult patients. Clin Infect Dis. 2008;47(1):105–8.CrossRefGoogle Scholar
  72. 72.
    Rouphael NG, et al. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7(12):814–22.CrossRefGoogle Scholar
  73. 73.
    Imashuku S, et al. Recent developments in the management of haemophagocytic lymphohistiocytosis. Expert Opin Pharmacother. 2001;2(9):1437–48.CrossRefGoogle Scholar
  74. 74.
    Imashuku S, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol. 2001;19(10):2665–73.CrossRefGoogle Scholar
  75. 75.
    Coca A, et al. Macrophage activation syndrome: serological markers and treatment with anti-thymocyte globulin. Clin Immunol. 2009;132(1):10–8.CrossRefGoogle Scholar
  76. 76.
    Mahlaoui N, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120(3):e622–8.CrossRefGoogle Scholar
  77. 77.
    Schulert GS, Grom AA. Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol. 2014;28(2):277–92.CrossRefGoogle Scholar
  78. 78.
    Matsumoto Y, et al. The efficacy of therapeutic plasmapheresis for the treatment of fatal hemophagocytic syndrome: two case reports. Ther Apher. 1998;2(4):300–4.CrossRefGoogle Scholar
  79. 79.
    Raschke RA, Garcia-Orr R. Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults. Chest. 2011;140(4):933–8.CrossRefGoogle Scholar
  80. 80.
    Jordan MB, Filipovich AH. Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step. Bone Marrow Transplant. 2008;42(7):433–7.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Bella Mehta
    • 1
    • 2
  • Petros Efthimiou
    • 3
    • 4
  1. 1.Weill Cornell MedicineNew YorkUSA
  2. 2.Hospital for Special SurgeryNew YorkUSA
  3. 3.New York University School of MedicineNew YorkUSA
  4. 4.NYU/Langone HealthNew YorkUSA

Personalised recommendations