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The History of Macrophage Activation Syndrome in Autoimmune Diseases

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Cytokine Storm Syndrome

Abstract

In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH), was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.

MAS is one of the many types of secondary HLH and should not be confused with primary HLH. Experience has taught that MAS secondary to different autoimmune diseases are not equal. In the 30 years since initial description in patients with sJIA, the clinical spectrum, diseases associated with MAS, therapy, and understanding the pathogenesis have all made significant gains. The diagnostic/classification criteria for MAS secondary to sJIA, SLE, RA, and KD differ based on the different laboratory abnormalities associated with each (Ahn et al. The Journal of Rheumatology 44:996–1003, 2017; Han et al. Annals of the Rheumatic Diseases 75:e44, 2016; Ravelli et al. Annals of the Rheumatic Diseases 75:481–9, 2016; Borgia et al. Arthritis and Rheumatology 70:616–24, 2018). These differnces include the thrombocytosis associated with sJIA, a chronic generalized activation of the immune system leading to such as elevations of fibrinogen and sIL-2R, and low platelet count associated with SLE, and the more acute inflammation associated with KD. Therefore, individual diagnostic criteria are required, and they all differ from the diagnostic criteria for HLH which are based on a non-activated immune system (Ahn et al. The Journal of Rheumatology 44:996–1003, 2017; Han et al. Annals of the Rheumatic Diseases 75:e44, 2016; Ravelli et al. Annals of the Rheumatic Diseases 75:481–9, 2016; Borgia et al. Arthritis and Rheumatology 70:616–24, 2018; Henter et al. Pediatric Blood and Cancer 48:124–31, 2007). This helps to explain why the HLH diagnostic criteria do not perform well in MAS.

The initial treatment remains high-dose steroids and IVIG followed by the use of a calcineurin inhibitor for more resistant cases. Advances in understanding the mechanisms leading to MAS, which has been greatly aided by the use of mouse models of MAS and advances in genome sequencing, offers a bright future for more specific therapies. These therapies are directed to specific cytokines involved in the pathogenesis of MAS and lead to decreases in the morbidity and mortality associated with MAS. IL-1 inhibition with anakinra has been shown to be effective in patients with MAS. In the future other anti-cytokine therapies will likely target the IL-18-IFN-γ axis. These more specific therapies may obviate the need for nonspecific immunosuppressive therapies including high dose prolonged steroids, calcineurin inhibitors, and etoposide.

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References

  1. Farquhar, J. W., & Claireaux, A. E. (1952). Familial haemophagocytic reticulosis. Archives of Disease in Childhood, 27, 519–525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Henter, J. I., Arico, M., Egeler, R. M., et al. (1997). HLH-94: A treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Medical and Pediatric Oncology, 28, 342–347.

    Article  CAS  PubMed  Google Scholar 

  3. Henter, J. I., Horne, A., Arico, M., et al. (2007). HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric Blood & Cancer, 48, 124–131.

    Article  Google Scholar 

  4. Scott, R., & Robb-Smith, A. (1939). Histiocytic medullary retiuculosis. Lancet, 2, 194–198.

    Article  Google Scholar 

  5. Cline, M. J., & Golde, D. W. (1973). A review and reevaluation of the histiocytic disorders. The American Journal of Medicine, 55, 49–60.

    Article  CAS  PubMed  Google Scholar 

  6. Risdall, R. J., McKenna, R. W., Nesbit, M. E., et al. (1979). Virus-associated hemophagocytic syndrome A benign histiocytic proliferation distinct from malignant histiocytosis. Cancer, 44, 993–1002.

    Article  CAS  PubMed  Google Scholar 

  7. Stark, B., Hershko, C., Rosen, N., Cividalli, G., Karsai, H., & Soffer, D. (1984). Familial hemophagocytic lymphohistiocytosis (FHLH) in Israel. I. Description of 11 patients of Iranian-Iraqi origin and review of the literature. Cancer, 54, 2109–2121.

    Article  CAS  PubMed  Google Scholar 

  8. Heaton, D. C., & Moller, P. W. (1985). Still’s disease associated with Coxsackie infection and haemophagocytic syndrome. Annals of the Rheumatic Diseases, 44, 341–344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Otrock, Z. K., Daver, N., Kantarjian, H. M., & Eby, C. S. (2017). Diagnostic challenges of hemophagocytic lymphohistiocytosis. Clinical Lymphoma, Myeloma & Leukemia, 17s, S105–Ss10.

    Article  Google Scholar 

  10. Parodi, A., Davi, S., Pringe, A. B., et al. (2009). Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty-eight patients. Arthritis and Rheumatism, 60, 3388–3399.

    Article  CAS  PubMed  Google Scholar 

  11. Hadchouel, M., Prieur, A. M., & Griscelli, C. (1985). Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: Possible relationship to drugs or infection. The Journal of Pediatrics, 106, 561–566.

    Article  CAS  PubMed  Google Scholar 

  12. Stephan, J. L., Zeller, J., Hubert, P., Herbelin, C., Dayer, J. M., & Prieur, A. M. (1993). Macrophage activation syndrome and rheumatic disease in childhood: A report of four new cases. Clinical and Experimental Rheumatology, 11, 451–456.

    CAS  PubMed  Google Scholar 

  13. Prieur, A. M., & Stephan, J. L. (1994). Macrophage activation syndrome in rheumatic diseases in children. Revue du Rhumatisme, 61, 447–451.

    CAS  PubMed  Google Scholar 

  14. Kornreich, H., Malouf, N. N., & Hanson, V. (1971). Acute hepatic dysfunction in juvenile rheumatoid arthritis. The Journal of Pediatrics, 79, 27–35.

    Article  CAS  PubMed  Google Scholar 

  15. De Vere-Tyndall, A., Macauley, D., & Ansell, B. M. (1983). Disseminated intravascular coagulation complicating systemic juvenile chronic arthritis (“Still’s disease”). Clinical Rheumatology, 2, 415–418.

    Article  PubMed  Google Scholar 

  16. Silverman, E. D., Miller 3rd, J. J., Bernstein, B., & Shafai, T. (1983). Consumption coagulopathy associated with systemic juvenile rheumatoid arthritis. The Journal of Pediatrics, 103, 872–876.

    Article  CAS  PubMed  Google Scholar 

  17. Morris, J. A., Adamson, A. R., Holt, P. J., & Davson, J. (1985). Still’s disease and the virus-associated haemophagocytic syndrome. Annals of the Rheumatic Diseases, 44, 349–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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. Annals of the Rheumatic Diseases, 75, 481–489.

    Article  CAS  PubMed  Google Scholar 

  19. Park, J. H., Seo, Y. M., Han, S. B., et al. (2016). Recurrent macrophage activation syndrome since toddler age in an adolescent boy with HLA B27 positive juvenile ankylosing spondylitis. Korean Journal of Pediatrics, 59, 421–424.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wong, K. F., Hui, P. K., Chan, J. K., Chan, Y. W., & Ha, S. Y. (1991). The acute lupus hemophagocytic syndrome. Annals of Internal Medicine, 114, 387–390.

    Article  CAS  PubMed  Google Scholar 

  21. Borgia, R. E., Gerstein, M., Levy, D. M., Silverman, E. D., & Hiraki, L. T. (2018). Features, treatment, and outcomes of macrophage activation syndrome in childhood-onset systemic lupus erythematosus. Arthritis & Rhematology, 70, 616–624.

    Article  CAS  Google Scholar 

  22. Granata, G., Didona, D., Stifano, G., Feola, A., & Granata, M. (2015). Macrophage activation syndrome as onset of systemic lupus erythematosus: A case report and a review of the literature. Case Reports in Medicine, 2015, 294041.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gavand, P. E., Serio, I., Arnaud, L., et al. (2017). Clinical spectrum and therapeutic management of systemic lupus erythematosus-associated macrophage activation syndrome: A study of 103 episodes in 89 adult patients. Autoimmunity Reviews, 16, 743–749.

    Article  CAS  PubMed  Google Scholar 

  24. Aytac, S., Batu, E. D., Unal, S., et al. (2016). Macrophage activation syndrome in children with systemic juvenile idiopathic arthritis and systemic lupus erythematosus. Rheumatology International, 36, 1421–1429.

    Article  CAS  PubMed  Google Scholar 

  25. Khan, F. Y., Morad, N. A., & Fawzy, Z. (2007). Kikuchi’s disease associated with hemophagocytosis. Chang Gung Medical Journal, 30, 370–373.

    PubMed  Google Scholar 

  26. Ohga, S., Ooshima, A., Fukushige, J., & Ueda, K. (1995). Histiocytic haemophagocytosis in a patient with Kawasaki disease: Changes in the hypercytokinaemic state. European Journal of Pediatrics, 154, 539–541.

    Article  CAS  PubMed  Google Scholar 

  27. Garcia-Pavon, S., Yamazaki-Nakashimada, M. A., Baez, M., Borjas-Aguilar, K. L., & Murata, C. (2017). Kawasaki disease complicated with macrophage activation syndrome: A systematic review. Journal of Pediatric Hematology/Oncology, 39, 445–451.

    Article  PubMed  Google Scholar 

  28. Choi, U. Y., Han, S. B., Lee, S. Y., & Jeong, D. C. (2017). Should refractory Kawasaki disease be considered occult macrophage activation syndrome? Seminars in Arthritis and Rheumatism, 46, e17.

    Article  PubMed  Google Scholar 

  29. Atteritano, M., David, A., Bagnato, G., et al. (2012). Haemophagocytic syndrome in rheumatic patients. A systematic review. European Review for Medical and Pharmacological Sciences, 16, 1414–1424.

    CAS  PubMed  Google Scholar 

  30. Kang, H. R., Kwon, Y. H., Yoo, E. S., et al. (2013). Clinical characteristics of hemophagocytic lymphohistiocytosis following Kawasaki disease: Differentiation from recurrent Kawasaki disease. Blood Research, 48, 254–257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Latino, G. A., Manlhiot, C., Yeung, R. S., Chahal, N., & McCrindle, B. W. (2010). Macrophage activation syndrome in the acute phase of Kawasaki disease. Journal of Pediatric Hematology/Oncology, 32, 527–531.

    Article  PubMed  Google Scholar 

  32. Han, S. B., Lee, S. Y., Jeong, D. C., & Kang, J. H. (2016). Should 2016 criteria for macrophage activation syndrome be applied in children with Kawasaki disease, as well as with systemic-onset juvenile idiopathic arthritis? Annals of the Rheumatic Diseases, 75, e44.

    Article  PubMed  CAS  Google Scholar 

  33. Crow, J., & Gumpel, J. M. (1977). Histiocytic medullary reticulosis presenting as rheumatoid arthritis. Proceedings of the Royal Society of Medicine, 70, 632–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Katoh, N., Gono, T., Mitsuhashi, S., et al. (2007). Hemophagocytic syndrome associated with rheumatoid arthritis. Internal Medicine, 46, 1809–1813.

    Article  PubMed  Google Scholar 

  35. Fukaya, S., Yasuda, S., Hashimoto, T., et al. (2008). Clinical features of haemophagocytic syndrome in patients with systemic autoimmune diseases: Analysis of 30 cases. Rheumatology, 47, 1686–1691.

    Article  CAS  PubMed  Google Scholar 

  36. Dhote, R., Simon, J., Papo, T., et al. (2003). Reactive hemophagocytic syndrome in adult systemic disease: Report of twenty-six cases and literature review. Arthritis and Rheumatism, 49, 633–639.

    Article  PubMed  Google Scholar 

  37. Basnet, A., & Cholankeril, M. R. (2014). Hemophagocytic lymphohistiocytosis in a patient with Goodpasture’s syndrome: A rare clinical association. American Journal of Case Reports, 15, 431–436.

    Article  PubMed  Google Scholar 

  38. Lou, Y. J., Jin, J., & Mai, W. Y. (2007). Ankylosing spondylitis presenting with macrophage activation syndrome. Clinical Rheumatology, 26, 1929–1930.

    Article  PubMed  Google Scholar 

  39. Ahn, S. S., Yoo, B. W., Jung, S. M., Lee, S. W., Park, Y. B., & Song, J. J. (2017). Application of the 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome in patients with adult-onset still disease. The Journal of Rheumatology, 44, 996–1003.

    Article  CAS  PubMed  Google Scholar 

  40. Fishman, D., Rooney, M., & Woo, P. (1995). Successful management of reactive haemophagocytic syndrome in systemic-onset juvenile chronic arthritis. British Journal of Rheumatology, 34, 888.

    Article  CAS  PubMed  Google Scholar 

  41. Quesnel, B., Catteau, B., Aznar, V., Bauters, F., & Fenaux, P. (1997). Successful treatment of juvenile rheumatoid arthritis associated haemophagocytic syndrome by cyclosporin A with transient exacerbation by conventional-dose G-CSF. British Journal of Haematology, 97, 508–510.

    CAS  PubMed  Google Scholar 

  42. Ravelli, A., Viola, S., De Benedetti, F., Magni-Manzoni, S., Tzialla, C., & Martini, A. (2001). Dramatic efficacy of cyclosporine A in macrophage activation syndrome. Clinical and Experimental Rheumatology, 19, 108.

    CAS  PubMed  Google Scholar 

  43. Prahalad, S., Bove, K. E., Dickens, D., Lovell, D. J., & Grom, A. A. (2001). Etanercept in the treatment of macrophage activation syndrome. The Journal of Rheumatology, 28, 2120–2124.

    CAS  PubMed  Google Scholar 

  44. Stabile, A., Bertoni, B., Ansuini, V., La Torraca, I., Salli, A., & Rigante, D. (2006). The clinical spectrum and treatment options of macrophage activation syndrome in the pediatric age. European Review for Medical and Pharmacological Sciences, 10, 53–59.

    CAS  PubMed  Google Scholar 

  45. Ozturk, K., & Ekinci, Z. (2015). Successful treatment of macrophage activation syndrome due to systemic onset juvenile idiopathic arthritis with antithymocyte globulin. Rheumatology International, 35, 1779–1780.

    Article  PubMed  Google Scholar 

  46. Tomaske, M., Amon, O., Bosk, A., Handgretinger, R., Schneider, E. M., & Niethammer, D. (2002). Alpha-CD25 antibody treatment in a child with hemophagocytic lymphohistiocytosis. Medical and Pediatric Oncology, 38, 141–142.

    Article  PubMed  Google Scholar 

  47. Olin, R. L., Nichols, K. E., Naghashpour, M., et al. (2008). Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lymphohistiocytosis. American Journal of Hematology, 83, 747–749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Behrens, E. M., Kreiger, P. A., Cherian, S., & Cron, R. Q. (2006). Interleukin 1 receptor antagonist to treat cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis. The Journal of Rheumatology, 33, 2081–2084.

    PubMed  Google Scholar 

  49. Durand, M., Troyanov, Y., Laflamme, P., & Gregoire, G. (2010). Macrophage activation syndrome treated with anakinra. The Journal of Rheumatology, 37, 879–880.

    Article  PubMed  Google Scholar 

  50. Miettunen, P. M., Narendran, A., Jayanthan, A., Behrens, E. M., & Cron, R. Q. (2011). 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, 50, 417–419.

    Article  CAS  PubMed  Google Scholar 

  51. Shakoory, B., Carcillo, J. A., Chatham, W. W., et al. (2016). Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: Reanalysis of a prior phase III trial. Critical Care Medicine, 44, 275–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kahn, P. J., & Cron, R. Q. (2013). Higher-dose Anakinra is effective in a case of medically refractory macrophage activation syndrome. The Journal of Rheumatology, 40, 743–744.

    Article  CAS  PubMed  Google Scholar 

  53. Prencipe, G., Caiello, I., Pascarella, A., et al. (2018). Neutralization of IFN-gamma reverts clinical and laboratory features in a mouse model of macrophage activation syndrome. The Journal of Allergy and Clinical Immunology, 141, 1439–1449.

    Article  CAS  PubMed  Google Scholar 

  54. Bracaglia, C., de Graaf, K., Pires Marafon, D., et al. (2017). Elevated circulating levels of interferon-gamma and interferon-gamma-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Annals of the Rheumatic Diseases, 76, 166–172.

    Article  CAS  PubMed  Google Scholar 

  55. Kawashima, M., Yamamura, M., Taniai, M., et al. (2001). Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still’s disease. Arthritis and Rheumatism, 44, 550–560.

    Article  CAS  PubMed  Google Scholar 

  56. Canna, S. W., de Jesus, A. A., Gouni, S., et al. (2014). An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nature Genetics, 46, 1140–1146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Canna, S. W., Girard, C., Malle, L., et al. (2017). Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. The Journal of Allergy and Clinical Immunology, 139, 1698–1701.

    Article  CAS  PubMed  Google Scholar 

  58. Shimizu, M., Nakagishi, Y., Inoue, N., et al. (2015). Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Clinical Immunology, 160, 277–281.

    Article  CAS  PubMed  Google Scholar 

  59. Girard-Guyonvarc’h, C., Palomo, J., Martin, P., et al. (2018). Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. Blood, 131, 1430–1441.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  61. Terrell, C. E., & Jordan, M. B. (2013). Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. Blood, 121, 5184–5191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kogl, T., Muller, J., Jessen, B., et al. (2013). Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell exhaustion limits fatal disease. Blood, 121, 604–613.

    Article  PubMed  CAS  Google Scholar 

  63. Sepulveda, F. E., Garrigue, A., Maschalidi, S., et al. (2016). Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice. Blood, 127, 2113–2121.

    Article  CAS  PubMed  Google Scholar 

  64. Behrens, E. M., Canna, S. W., Slade, K., et al. (2011). Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. The Journal of Clinical Investigation, 121, 2264–2277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Brown, D. E., McCoy, M. W., Pilonieta, M. C., Nix, R. N., & Detweiler, C. S. (2010). Chronic murine typhoid fever is a natural model of secondary hemophagocytic lymphohistiocytosis. PLoS One, 5, e9441.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Buatois, V., Chatel, L., Cons, L., et al. (2017). Use of a mouse model to identify a blood biomarker for IFNgamma activity in pediatric secondary hemophagocytic lymphohistiocytosis. Translational Research, 180, 37–52.e2.

    Article  CAS  PubMed  Google Scholar 

  67. Brisse, E., Imbrechts, M., Put, K., et al. (2016). Mouse cytomegalovirus infection in BALB/c mice resembles virus-associated secondary hemophagocytic lymphohistiocytosis and shows a pathogenesis distinct from primary hemophagocytic lymphohistiocytosis. Journal of Immunology, 196, 3124–3134.

    Article  CAS  Google Scholar 

  68. Sato, K., Misawa, N., Nie, C., et al. (2011). A novel animal model of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in humanized mice. Blood, 117, 5663–5673.

    Article  CAS  PubMed  Google Scholar 

  69. Maschalidi, S., Sepulveda, F. E., Garrigue, A., Fischer, A., & de Saint Basile, G. (2016). Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood, 128, 60–71.

    Article  CAS  PubMed  Google Scholar 

  70. Das, R., Guan, P., Sprague, L., et al. (2016). Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood, 127, 1666–1675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chiossone, L., Audonnet, S., Chetaille, B., et al. (2012). Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein. Frontiers in Immunology, 3, 239.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Stepp, S. E., Dufourcq-Lagelouse, R., Le Deist, F., et al. (1999). Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science, 286, 1957–1959.

    Article  CAS  PubMed  Google Scholar 

  73. Cetica, V., Sieni, E., Pende, D., et al. (2016). Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry. The Journal of Allergy and Clinical Immunology, 137, 188–96.e4.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Mukda, E., Trachoo, O., Pasomsub, E., et al. (2017). Exome sequencing for simultaneous mutation screening in children with hemophagocytic lymphohistiocytosis. International Journal of Hematology, 106, 282–290.

    Article  CAS  PubMed  Google Scholar 

  75. Rigante, D., Emmi, G., Fastiggi, M., Silvestri, E., & Cantarini, L. (2015). Macrophage activation syndrome in the course of monogenic autoinflammatory disorders. Clinical Rheumatology, 34, 1333–1339.

    Article  PubMed  Google Scholar 

  76. Hazen, M. M., Woodward, A. L., Hofmann, I., et al. (2008). Mutations of the hemophagocytic lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis and Rheumatism, 58, 567–570.

    Article  CAS  PubMed  Google Scholar 

  77. Zhang, K., Biroschak, J., Glass, D. N., et al. (2008). Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis and Rheumatism, 58, 2892–2896.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Vastert, S. J., van Wijk, R., D’Urbano, L. E., et al. (2010). Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology, 49, 441–449.

    Article  CAS  PubMed  Google Scholar 

  79. Kaufman, K. M., Linghu, B., Szustakowski, J. D., et al. (2014). Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis & Rhematology, 66, 3486–3495.

    Article  CAS  Google Scholar 

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  1. Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Earl D. Silverman

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    Randy Q. Cron

  2. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Edward M. Behrens

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Silverman, E.D. (2019). The History of Macrophage Activation Syndrome in Autoimmune Diseases. In: Cron, R., Behrens, E. (eds) Cytokine Storm Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-030-22094-5_2

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