Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Abstract

Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30–40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro- and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  1. Grom AA, Passo M . Macrophage activation syndrome in systemic juvenile rheumatoid arthritis. J Pediatr 1996; 129: 630–632.

    CAS  PubMed  Google Scholar 

  2. Prieur AM, Stephan JL . [Macrophage activation syndrome in rheumatic diseases in children]. Rev Rhum Ed Fr 1994; 61: 447–451.

    CAS  PubMed  Google Scholar 

  3. Sawhney S, Woo P, Murray KJ . Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001; 85: 421–426.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Parodi A, Davi S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum 2009; 60: 3388–3399.

    CAS  PubMed  Google Scholar 

  5. Avcin T, Tse SM, Schneider R, Ngan B, Silverman ED . Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood. J Pediatr 2006; 148: 683–686.

    PubMed  Google Scholar 

  6. Latino GA, Manlhiot C, Yeung RS, Chahal N, McCrindle BW . Macrophage activation syndrome in the acute phase of Kawasaki disease. J Pediatr Hematol Oncol 2010; 32: 527–531.

    PubMed  Google Scholar 

  7. Simonini G, Pagnini I, Innocenti L, Calabri GB, De Martino M, Cimaz R . Macrophage activation syndrome/hemophagocytic lymphohistiocytosis and Kawasaki disease. Pediatr Blood Cancer 2010; 55: 592.

    PubMed  Google Scholar 

  8. Rigante D, Capoluongo E, Bertoni B, Ansuini V, Chiaretti A, Piastra M et al. First report of macrophage activation syndrome in hyperimmunoglobulinemia D with periodic fever syndrome. Arthritis Rheum 2007; 56: 658–661.

    PubMed  Google Scholar 

  9. Rossi-Semerano L, Hermeziu B, Fabre M, Kone-Paut I . Macrophage activation syndrome revealing familial Mediterranean fever. Arthritis Care Res (Hoboken) 2010; 63: 780–783.

    Google Scholar 

  10. Buoncompagni A, Loy A, Sala I, Ravelli A . The paradox of macrophage activation syndrome triggered by biologic medications. Pediatr Rhematol Online J 2005; 3: 70–73.

    Google Scholar 

  11. Athreya BH . Is macrophage activation syndrome a new entity? Clin Exp Rheumatol 2002; 20: 121–123.

    CAS  PubMed  Google Scholar 

  12. Ramanan AV, Schneider R . Macrophage activation syndrome—what's in a name!. J Rheumatol 2003; 30: 2513–2516.

    PubMed  Google Scholar 

  13. Behrens EM, Beukelman T, Paessler M, Cron RQ . Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol 2007; 34: 1133–1138.

    PubMed  Google Scholar 

  14. Bleesing J, Prada A, Siegel DM, Villanueva J, Olson J, Ilowite NT et al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum 2007; 56: 965–971.

    CAS  PubMed  Google Scholar 

  15. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48: 124–131.

    PubMed  Google Scholar 

  16. Pelkonen P, Swanljung K, Siimes MA . Ferritinemia as an indicator of systemic disease activity in children with systemic juvenile rheumatoid arthritis. Acta Paediatr Scand 1986; 75: 64–68.

    CAS  PubMed  Google Scholar 

  17. Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr 2005; 146: 598–604.

    PubMed  Google Scholar 

  18. Gupta A, Tyrrell P, Valani R, Benseler S, Weitzman S, Abdelhaleem M . The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008; 51: 402–404.

    PubMed  Google Scholar 

  19. Davi S, Consolaro A, Guseinova D, Pistorio A, Ruperto N, Martini A et al. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol 2011; 38: 764–768.

    PubMed  Google Scholar 

  20. Ramanan AV, Baildam EM . Macrophage activation syndrome is hemophagocytic lymphohistiocytosis--need for the right terminology. J Rheumatol 2002; 29: 1105; author reply 1105.

    PubMed  Google Scholar 

  21. Filipovich AH . Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009: 127–131.

    Google Scholar 

  22. Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M et al. Contemporary classification of histiocytic disorders. The WHO Committee on Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997; 29: 157–166.

    CAS  PubMed  Google Scholar 

  23. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial hemophagocytic lymphohistiocytosis. Blood 2011; 118: 5794–5798.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sullivan KE, Delaat CA, Douglas SD, Filipovich AH . Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and in first degree relatives. Pediatr Res 1998; 44: 465–468.

    CAS  PubMed  Google Scholar 

  25. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003; 115: 461–473.

    CAS  PubMed  Google Scholar 

  26. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999; 286: 1957–1959.

    CAS  PubMed  Google Scholar 

  27. zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 2009; 85: 482–492.

    PubMed  PubMed Central  Google Scholar 

  28. zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 2005; 14: 827–834.

    CAS  PubMed  Google Scholar 

  29. Menasche G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 2000; 25: 173–176.

    CAS  PubMed  Google Scholar 

  30. Barbosa MD, Nguyen QA, Tchernev VT, Ashley JA, Detter JC, Blaydes SM et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature 1996; 382: 262–265.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 1998; 20: 129–135.

    CAS  PubMed  Google Scholar 

  32. Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB et al. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood 2010; 116: 1079–1082.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Jordan MB, Hildeman D, Kappler J, Marrack P . An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 2004; 104: 735–743.

    CAS  PubMed  Google Scholar 

  34. Kagi D, Odermatt B, Mak TW . Homeostatic regulation of CD8+ T cells by perforin. Eur J Immunol 1999; 29: 3262–3272.

    CAS  PubMed  Google Scholar 

  35. Lykens JE, Terrell CE, Zoller EE, Risma K, Jordan MB . Perforin is a critical physiologic regulator of T-cell activation. Blood 2011; 118: 618–626.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Menasche G, Feldmann J, Fischer A, de Saint Basile G . Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev 2005; 203: 165–179.

    CAS  PubMed  Google Scholar 

  37. Behrens EM . Macrophage activation syndrome in rheumatic disease: what is the role of the antigen presenting cell? Autoimmun Rev 2008; 7: 305–308.

    CAS  PubMed  Google Scholar 

  38. 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; 105: 1648–1651.

    CAS  PubMed  Google Scholar 

  39. Grom AA, Villanueva J, Lee S, Goldmuntz EA, Passo MH, Filipovich A . Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J Pediatr 2003; 142: 292–296.

    CAS  PubMed  Google Scholar 

  40. Vastert SJ, van Wijk R, D′Urbano LE, de Vooght KM, de Jager W, Ravelli A et al. Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology (Oxford) 2010; 49: 441–449.

    CAS  Google Scholar 

  41. Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A et al. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther 2005; 7: R30–R37.

    CAS  PubMed  Google Scholar 

  42. Zhang K, Biroschak J, Glass DN, Thompson SD, Finkel T, Passo MH et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum 2008; 58: 2892–2896.

    PubMed  PubMed Central  Google Scholar 

  43. Hazen MM, Woodward AL, Hofmann I, Degar BA, Grom A, Filipovich AH et al. Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis Rheum 2008; 58: 567–570.

    CAS  PubMed  Google Scholar 

  44. Pivot-Pajot C, Varoqueaux F, de Saint Basile G, Bourgoin SG . Munc13-4 regulates granule secretion in human neutrophils. J Immunol 2008; 180: 6786–6797.

    CAS  PubMed  Google Scholar 

  45. Ren Q, Wimmer C, Chicka MC, Ye S, Ren Y, Hughson FM et al. Munc13-4 is a limiting factor in the pathway required for platelet granule release and hemostasis. Blood 2010; 116: 869–877.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang K, Johnson JA, Biroschak J, Villanueva J, Lee SM, Bleesing JJ et al. Familial haemophagocytic lymphohistiocytosis in patients who are heterozygous for the A91V perforin variation is often associated with other genetic defects. Int J Immunogenet 2007; 34: 231–233.

    CAS  PubMed  Google Scholar 

  47. Yanagimachi M, Naruto T, Miyamae T, Hara T, Kikuchi M, Hara R et al. Association of IRF5 polymorphisms with susceptibility to macrophage activation syndrome in patients with juvenile idiopathic arthritis. J Rheumatol 2011; 38: 769–774.

    CAS  PubMed  Google Scholar 

  48. Stinchcombe JC, Barral DC, Mules EH, Booth S, Hume AN, Machesky LM et al. Rab27a is required for regulated secretion in cytotoxic T lymphocytes. J Cell Biol 2001; 152: 825–834.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Crozat K, Hoebe K, Ugolini S, Hong NA, Janssen E, Rutschmann S et al. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J Exp Med 2007; 204: 853–863.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Pachlopnik Schmid J, Ho CH, Chretien F, Lefebvre JM, Pivert G, Kosco-Vilbois M et al. Neutralization of IFNgamma defeats haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice. EMBO Mol Med 2009; 1: 112–124.

    PubMed  Google Scholar 

  51. Pachlopnik Schmid J, Ho CH, Diana J, Pivert G, Lehuen A, Geissmann F et al. A Griscelli syndrome type 2 murine model of hemophagocytic lymphohistiocytosis (HLH). Eur J Immunol 2008; 38: 3219–3225.

    PubMed  Google Scholar 

  52. Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest 2011; 121: 2264–2277.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Fall N, Barnes M, Thornton S, Luyrink L, Olson J, Ilowite NT et al. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum 2007; 56: 3793–3804.

    CAS  PubMed  Google Scholar 

  54. Ewald SE, Barton GM . Nucleic acid sensing Toll-like receptors in autoimmunity. Curr Opin Immunol 2011; 23: 3–9.

    CAS  PubMed  Google Scholar 

  55. Guggemoos S, Hangel D, Hamm S, Heit A, Bauer S, Adler H . TLR9 contributes to antiviral immunity during gammaherpesvirus infection. J Immunol 2008; 180: 438–443.

    CAS  PubMed  Google Scholar 

  56. Teramura T, Tabata Y, Yagi T, Morimoto A, Hibi S, Imashuku S . Quantitative analysis of cell-free Epstein-Barr virus genome copy number in patients with EBV-associated hemophagocytic lymphohistiocytosis. Leuk Lymphoma 2002; 43: 173–179.

    CAS  PubMed  Google Scholar 

  57. Sumegi J, Barnes MG, Nestheide SV, Molleran-Lee S, Villanueva J, Zhang K et al. Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis. Blood 2011; 117: e151–e160.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Fife MS, Gutierrez A, Ogilvie EM, Stock CJ, Samuel JM, Thomson W et al. Novel IL10 gene family associations with systemic juvenile idiopathic arthritis. Arthritis Res Ther 2006; 8: R148.

    PubMed  PubMed Central  Google Scholar 

  59. Moller JC, Paul D, Ganser G, Range U, Gahr M, Kelsch R et al. IL10 promoter polymorphisms are associated with systemic onset juvenile idiopathic arthritis (SoJIA). Clin Exp Rheumatol 2010; 28: 912–918.

    CAS  PubMed  Google Scholar 

  60. Krebs P, Crozat K, Popkin D, Oldstone MB, Beutler B . Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. Blood 2011; 117: 6582–6588.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hayashi K, Jin Z, Onoda S, Joko H, Teramoto N, Ohara N et al. Rabbit model for human EBV-associated hemophagocytic syndrome (HPS): sequential autopsy analysis and characterization of IL-2-dependent cell lines established from herpesvirus papio-induced fatal rabbit lymphoproliferative diseases with HPS. Am J Pathol 2003; 162: 1721–1736.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Hsieh WC, Chang Y, Hsu MC, Lan BS, Hsiao GC, Chuang HC et al. Emergence of anti-red blood cell antibodies triggers red cell phagocytosis by activated macrophages in a rabbit model of Epstein-Barr virus-associated hemophagocytic syndrome. Am J Pathol 2007; 170: 1629–1639.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Chan CB, Abe M, Hashimoto N, Hao C, Williams IR, Liu X et al. Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome. Proc Natl Acad Sci USA 2009; 106: 468–473.

    CAS  PubMed  Google Scholar 

  64. Yin L, Al-Alem U, Liang J, Tong WM, Li C, Badiali M et al. Mice deficient in the X-linked lymphoproliferative disease gene sap exhibit increased susceptibility to murine gammaherpesvirus-68 and hypo-gammaglobulinemia. J Med Virol 2003; 71: 446–455.

    CAS  PubMed  Google Scholar 

  65. Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R et al. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J Exp Med 2000; 192: 337–346.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Brown DE, McCoy MW, Pilonieta MC, Nix RN, Detweiler CS . Chronic murine typhoid fever is a natural model of secondary hemophagocytic lymphohistiocytosis. PLoS One 2010; 5: e9441.

    PubMed  PubMed Central  Google Scholar 

  67. Yanaba K, Bouaziz JD, Matsushita T, Tsubata T, Tedder TF . The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol 2009; 182: 7459–7472.

    CAS  PubMed  Google Scholar 

  68. Zoller EE, Lykens JE, Terrell CE, Aliberti J, Filipovich AH, Henson PM et al. Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med 2011; 208: 1203–1214.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Schaer DJ, Schaer CA, Schoedon G, Imhof A, Kurrer MO . Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis. Eur J Haematol 2006; 77: 432–436.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hadchouel M, Prieur AM, Griscelli C . Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection. J Pediatr 1985; 106: 561–566.

    CAS  PubMed  Google Scholar 

  71. Zeng HS, Xiong XY, Wei YD, Wang HW, Luo XP . Macrophage activation syndrome in 13 children with systemic-onset juvenile idiopathic arthritis. World J Pediatr 2008; 4: 97–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Singh S, Chandrakasan S, Ahluwalia J, Suri D, Rawat A, Ahmed N et al. Macrophage activation syndrome in children with systemic onset juvenile idiopathic arthritis: clinical experience from northwest India. Rheumatol Int (in press).

  73. Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM . Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr 1996; 129: 750–754.

    CAS  PubMed  Google Scholar 

  74. Quesnel B, Catteau B, Aznar V, Bauters F, Fenaux P . Successful treatment of juvenile rheumatoid arthritis associated haemophagocytic syndrome by cyclosporin A with transient exacerbation by conventional-dose G-CSF. Br J Haematol 1997; 97: 508–510.

    CAS  PubMed  Google Scholar 

  75. Ravelli A, De Benedetti F, Viola S, Martini A . Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr 1996; 128: 275–278.

    CAS  PubMed  Google Scholar 

  76. Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM . Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford) 2001; 40: 1285–1292.

    CAS  Google Scholar 

  77. Rao A, Luo C, Hogan PG . Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 1997; 15: 707–747.

    CAS  PubMed  Google Scholar 

  78. Wallace CA, Sherry DD . Trial of intravenous pulse cyclophosphamide and methylprednisolone in the treatment of severe systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum 1997; 40: 1852–1855.

    CAS  PubMed  Google Scholar 

  79. Henter JI, Samuelsson-Horne A, Arico M, Egeler RM, Elinder G, Filipovich AH et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002; 100: 2367–2373.

    CAS  PubMed  Google Scholar 

  80. Kishimoto T, Hamazaki T, Yasui M, Sasabe M, Okamura T, Sakata N et al. Autologous hematopoietic stem cell transplantation for 3 patients with severe juvenile rheumatoid arthritis. Int J Hematol 2003; 78: 453–456.

    PubMed  Google Scholar 

  81. Brinkman DM, de Kleer IM, ten Cate R, van Rossum MA, Bekkering WP, Fasth A et al. Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: long-term follow-up of a prospective clinical trial. Arthritis Rheum 2007; 56: 2410–2421.

    CAS  PubMed  Google Scholar 

  82. Emmenegger U, Frey U, Reimers A, Fux C, Semela D, Cottagnoud P et al. Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol 2001; 68: 4–10.

    CAS  PubMed  Google Scholar 

  83. Chen RL, Lin KH, Lin DT, Su IJ, Huang LM, Lee PI et al. Immunomodulation treatment for childhood virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol 1995; 89: 282–290.

    CAS  PubMed  Google Scholar 

  84. Larroche C, Bruneel F, Andre MH, Bader-Meunier B, Baruchel A, Tribout B et al. [Intravenously administered gamma-globulins in reactive hemaphagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP]. Ann Med Interne (Paris) 2000; 151: 533–539.

    CAS  Google Scholar 

  85. Tristano AG, Casanova-Escalona L, Torres A, Rodriguez MA . Macrophage activation syndrome in a patient with systemic onset rheumatoid arthritis: rescue with intravenous immunoglobulin therapy. J Clin Rheumatol 2003; 9: 253–258.

    PubMed  Google Scholar 

  86. Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ . Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford) 2011; 50: 417–419.

    CAS  Google Scholar 

  87. Mahlaoui N, Ouachee-Chardin M, de Saint Basile G, Neven B, Picard C, Blanche S et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics 2007; 120: e622–e628.

    PubMed  Google Scholar 

  88. Coca A, Bundy KW, Marston B, Huggins J, Looney RJ . Macrophage activation syndrome: serological markers and treatment with anti-thymocyte globulin. Clin Immunol 2009; 132: 10–18.

    CAS  PubMed  Google Scholar 

  89. Gurcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed AR . A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 2009; 9: 10–25.

    PubMed  Google Scholar 

  90. Alexeeva EI, Valieva SI, Bzarova TM, Semikina EL, Isaeva KB, Lisitsyn AO et al. Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis. Clin Rheumatol 2011; 30: 1163–1172.

    PubMed  Google Scholar 

  91. Balamuth NJ, Nichols KE, Paessler M, Teachey DT . 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: 569–573.

    PubMed  Google Scholar 

  92. Bosman G, Langemeijer SM, Hebeda KM, Raemaekers JM, Pickkers P, van der Velden WJ . The role of rituximab in a case of EBV-related lymphoproliferative disease presenting with haemophagocytosis. Neth J Med 2009; 67: 364–365.

    CAS  PubMed  Google Scholar 

  93. Aeberli D, Oertle S, Mauron H, Reichenbach S, Jordi B, Villiger PM . 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: 414–422.

    CAS  PubMed  Google Scholar 

  94. Emmenegger U, Reimers A, Frey U, Fux C, Bihl F, Semela D et al. Reactive macrophage activation syndrome: a simple screening strategy and its potential in early treatment initiation. Swiss Med Wkly 2002; 132: 230–236.

    CAS  PubMed  Google Scholar 

  95. Henzan T, Nagafuji K, Tsukamoto H, Miyamoto T, Gondo H, Imashuku S et al. Success with infliximab in treating refractory hemophagocytic lymphohistiocytosis. Am J Hematol 2006; 81: 59–61.

    PubMed  Google Scholar 

  96. Maeshima K, Ishii K, Iwakura M, Akamine M, Hamasaki H, Abe I et al. Adult-onset Still's disease with macrophage activation syndrome successfully treated with a combination of methotrexate and etanercept. Mod Rheumatol 2012; 22: 137–141.

    PubMed  Google Scholar 

  97. Makay B, Yilmaz S, Turkyilmaz Z, Unal N, Oren H, Unsal E . Etanercept for therapy-resistant macrophage activation syndrome. Pediatr Blood Cancer 2008; 50: 419–421.

    PubMed  Google Scholar 

  98. Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom AA . Etanercept in the treatment of macrophage activation syndrome. J Rheumatol 2001; 28: 2120–2124.

    CAS  PubMed  Google Scholar 

  99. Sellmer A, Stausbol-Gron B, Krag-Olsen B, Herlin T . Successful use of infliximab in macrophage activation syndrome with severe CNS involvement. Scand J Rheumatol 2011; 40: 156–157.

    CAS  PubMed  Google Scholar 

  100. Takahashi N, Naniwa T, Banno S . Successful use of etanercept in the treatment of acute lupus hemophagocytic syndrome. Mod Rheumatol 2008; 18: 72–75.

    PubMed  Google Scholar 

  101. Verbsky JW, Grossman WJ . Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives. Ann Med 2006; 38: 20–31.

    CAS  PubMed  Google Scholar 

  102. Chauveau E, Terrier F, Casassus-Buihle D, Moncoucy X, Oddes B . [Macrophage activation syndrome after treatment with infliximab for fistulated Crohn′s disease]. Presse Med 2005; 34: 583–584.

    PubMed  Google Scholar 

  103. Kaneko K, Kaburaki M, Muraoka S, Tanaka N, Yamamoto T, Kusunoki Y et al. Exacerbation of adult-onset Still′s disease, possibly related to elevation of serum tumor necrosis factor-alpha after etanercept administration. Int J Rheum Dis 2010; 13: e67–e69.

    PubMed  Google Scholar 

  104. Kimura Y, Pinho P, Walco G, Higgins G, Hummell D, Szer I et al. Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis. J Rheumatol 2005; 32: 935–942.

    CAS  PubMed  Google Scholar 

  105. Nadia EA, Carvalho JF, Bonfa E, Lotito AP, Silva CA . Macrophage activation syndrome associated with etanercept in a child with systemic onset juvenile idiopathic arthritis. Isr Med Assoc J 2009; 11: 635–636.

    PubMed  Google Scholar 

  106. Ramanan AV, Schneider R . Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol 2003; 30: 401–403.

    PubMed  Google Scholar 

  107. Sandhu C, Chesney A, Piliotis E, Buckstein R, Koren S . Macrophage activation syndrome after etanercept treatment. J Rheumatol 2007; 34: 241–242.

    PubMed  Google Scholar 

  108. Sterba G, Sterba Y, Stempel C, Blank J, Azor E, Gomez L . Macrophage activation syndrome induced by etanercept in a patient with systemic sclerosis. Isr Med Assoc J 2010; 12: 443–445.

    PubMed  Google Scholar 

  109. 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: 252–256.

    CAS  PubMed  Google Scholar 

  110. Agarwal S, Moodley J, Ajani Goel G, Theil KS, Mahmood SS, Lang RS . A rare trigger for macrophage activation syndrome. Rheumatol Int 2011; 31: 405–407.

    PubMed  Google Scholar 

  111. Molto A, Mateo L, Lloveras N, Olive A, Minguez S . Visceral leishmaniasis and macrophagic activation syndrome in a patient with rheumatoid arthritis under treatment with adalimumab. Joint Bone Spine 2010; 77: 271–273.

    PubMed  Google Scholar 

  112. Behrens EM, Kreiger PA, Cherian S, Cron RQ . Interleukin 1 receptor antagonist to treat cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis. J Rheumatol 2006; 33: 2081–2084.

    PubMed  Google Scholar 

  113. Verbsky JW, White AJ . Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol 2004; 31: 2071–2075.

    PubMed  Google Scholar 

  114. Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J . Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005; 201: 1479–1486.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA 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: 545–555.

    CAS  PubMed  Google Scholar 

  116. Bruck N, Suttorp M, Kabus M, Heubner G, Gahr M, Pessler F . Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol 2011; 17: 23–27.

    PubMed  Google Scholar 

  117. Kelly A, Ramanan AV . A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol 2008; 4: 615–620.

    CAS  PubMed  Google Scholar 

  118. Record JL, Beukelman T, Cron RQ . Combination therapy of abatacept and anakinra in children with refractory systemic juvenile idiopathic arthritis: a retrospective case series. J Rheumatol 2011; 38: 180–181.

    PubMed  Google Scholar 

  119. Burgi U, Mendez A, Hasler P, Hullstrung HD . Hemophagocytic syndrome in adult-onset Still′s disease (AOSD): a must for biologics?-Case report and brief review of the literature. Rheumatol Int (in press).

  120. Chou RC, Dinarello CA, Ferry JA, Dal Cin P . A 36-year-old woman with recurrent high-grade fevers, hypotension, and hypertriglyceridemia. Arthritis Care Res (Hoboken) 2010; 62: 128–136.

    Google Scholar 

  121. Debiais S, Maillot F, Luca L, Buret J, Fautrel B, Renard JP . Efficacy of anakinra in a case of refractory Still disease. J Clin Rheumatol 2008; 14: 357–358.

    PubMed  Google Scholar 

  122. Durand M, Troyanov Y, Laflamme P, Gregoire G . Macrophage activation syndrome treated with anakinra. J Rheumatol 2010; 37: 879–880.

    PubMed  Google Scholar 

  123. Fitzgerald AA, Leclercq SA, Yan A, Homik JE, Dinarello CA . Rapid responses to anakinra in patients with refractory adult-onset Still′s disease. Arthritis Rheum 2005; 52: 1794–1803.

    CAS  PubMed  Google Scholar 

  124. Kalliolias GD, Georgiou PE, Antonopoulos IA, Andonopoulos AP, Liossis SN . Anakinra treatment in patients with adult-onset Still′s disease is fast, effective, safe and steroid sparing: experience from an uncontrolled trial. Ann Rheum Dis 2007; 66: 842–843.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Maier J, Birkenfeld G, Pfirstinger J, Scholmerich J, Fleck M, Bruhl H . Effective treatment of steroid refractory adult-onset Still′s disease with anakinra. J Rheumatol 2008; 35: 939–941.

    CAS  PubMed  Google Scholar 

  126. Mehta BM, Hashkes PJ, Avery R, Deal CL . A 21-year-old man with Still′s disease with fever, rash, and pancytopenia. Arthritis Care Res (Hoboken) 2010; 62: 575–579.

    Google Scholar 

  127. Naumann L, Feist E, Natusch A, Langen S, Krause A, Buttgereit F et al. IL1-receptor antagonist anakinra provides long-lasting efficacy in the treatment of refractory adult-onset Still′s disease. Ann Rheum Dis 2010; 69: 466–467.

    CAS  PubMed  Google Scholar 

  128. Youssef J, Lazaro E, Blanco P, Viallard JF . Blockade of interleukin 1 receptor in Still′s disease affects activation of peripheral T-lymphocytes. J Rheumatol 2008; 35: 2453–2456.

    PubMed  Google Scholar 

  129. Clark SR, McMahon CJ, Gueorguieva I, Rowland M, Scarth S, Georgiou R et al. Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations. J Cereb Blood Flow Metab 2008; 28: 387–394.

    CAS  PubMed  Google Scholar 

  130. Fisher Jr CJ, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994; 271: 1836–1843.

    PubMed  Google Scholar 

  131. Canna S, Frankovich J, Higgins G, Narkewicz MR, Nash SR, Hollister JR et al. Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist. Pediatr Rheumatol Online J 2009; 7: 21.

    PubMed  PubMed Central  Google Scholar 

  132. Lurati A, Teruzzi B, Salmaso A, Demarco G, Pontikaki I, Gattinara M et al. Macrophage activation syndrome (MAS) during anti-IL1 therapy (anakinra) in a patient affected by systemic juvenile arthritis (soJIA): a report and review of the literature. Pediatr Rheumatol Online J 2005; 3: 79–85.

    Google Scholar 

  133. Zeft A, Hollister R, LaFleur B, Sampath P, Soep J, McNally B et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol 2009; 15: 161–164.

    PubMed  Google Scholar 

  134. Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008; 371: 998–1006.

    CAS  PubMed  Google Scholar 

  135. Kobayashi M, Takahashi Y, Yamashita H, Kaneko H, Mimori A . Benefit and a possible risk of tocilizumab therapy for adult-onset Still′s disease accompanied by macrophage-activation syndrome. Mod Rheumatol 2011; 21: 92–96.

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank the members of the International Macrophage Activation Syndrome Study Group for their expertise, collegiality and research efforts. We are also indebted to sJIA and MAS patients and their families for their willing participation in research and acceptance of novel life-sparing therapies. Dr Grom was supported in part by an NIH/NIAMS grant (R01AR059049), Dr Behrens was supported by an Arthritis Foundation Innovative Research Grant and Dr Cron was supported in part by the Arthritis Foundation, Alabama Chapter Endowed Chair in Pediatric Rheumatology.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R Q Cron.

Ethics declarations

Competing interests

Drs Cron and Behrens who serve as consultants to Genentech for the use of Actemra (tocilizumab) to treat sJIA. Dr Cron also serves as a consultant to Novartis on the use of canakinumab to treat sJIA. Other authors declare no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ravelli, A., Grom, A., Behrens, E. et al. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun 13, 289–298 (2012). https://doi.org/10.1038/gene.2012.3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2012.3

Keywords

  • macrophage activation syndrome
  • systemic juvenile idiopathic arthritis
  • hemophagocytosis
  • cytolysis
  • interferon-gamma
  • interleukin-1

Further reading

Search

Quick links