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Macrophage Activation Syndrome in SJIA - Alexei Grom

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This talk was given by Dr. Alexei Grom of Cincinnati Childrens Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.

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Macrophage Activation Syndrome in SJIA - Alexei Grom

  1. 1. Macrophage Activation Syndrome in SJIA Alexei Grom, MD Cincinnati Children’s Hospital Medical Center
  2. 2. Macrophage Activation Syndrome • Caused by excessive activation and multiplication of predominately two types of immune cells • cytotoxic CD8+ T cells and • macrophages • Excessive activation of these cell leads to massive inflammation that might be life-threatening
  3. 3. Normal macrophages • a type of white blood cells that engulfs and destroys microbes and other foreign substances in a process called phagocytosis
  4. 4. Macrophages in MAS • Overly activated • Start phagocytosing and destroying normal blood cells (such as red blood cells, neutrophils and platelets) • Destruction of these blood cells leads to a sudden drop in their numbers and might be life-threatening
  5. 5. Normal cytotoxic T cells • A cytotoxic T cell (also known CD8+ T-cell or killer T cell) is a T lymphocyte (another type of white blood cells) that kills cancer cells, and cells that are infected (particularly with viruses)
  6. 6. Annual Reviews
  7. 7. MAS is a cytokine storm
  8. 8. MAS is a cytokine storm • Immune cells communicate with each other by sending various “chemical signals” called cytokines • some cytokines cause inflammation • some cytokines reduce inflammation • In MAS, there is excessive activation and multiplication of macrophages and cytotoxic T cells that produce too much cytokines that cause inflammation
  9. 9. MΦ Proposed Mechanisms of Macrophage Activation in Hemophagocytic Syndromes 11 CD8+ IFN-γ GM-CSF MΦ MΦ MΦ MΦ MΦMΦ MΦ Mo TNF-α IL-6 IL-1 IL-18 M-CSF CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ MΦ
  10. 10. MAS and Hemophagocytic Lymphohistiocytosis • striking clinical similarities between MAS and hemophagocytic lymphohistiocytosis • hemophagocytic lymphohistiocytosis is a genetic disease in which cytotoxic cells have decreased ability to kill cells infected with viruses • Mouy R, et al. J Pediatr 1996;129:750
  11. 11. Annual Reviews
  12. 12. MΦ Proposed Mechanisms of Macrophage Activation in Hemophagocytic Syndromes 14 CD8+ IFN-γ GM-CSF MΦ MΦ MΦ MΦ MΦMΦ MΦ Mo TNF-α IL-6 IL-1 IL-18 M-CSF CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ MΦ CD8+ CD8+
  13. 13. Cytolytic Defects in FHLH Cytolytic cells cause destruction of target cells by delivering granules that contain proteins such as perforin and granzymes 15 death Infected Cell Effector Cell (NK Cell) Granzyme B Fusion Priming Munc13-4 Munc18-2 Syntaxin 11 Rab27a Nucleus Perforin
  14. 14. Signs and Symptoms Macrophage Activation Syndrome
  15. 15. Macrophage Activation Syndrome • Patients look very ill, run high fevers • Laboratory abnormalities: • Sudden drop in hemoglobin, platelet and neutrophil counts • Very high serum ferritin • Impaired liver function • Increased liver enzymes (Ast, Alt) • Decreased ability to make proteins involved in blood coagulation (such as fibrinogen) leading to bleeding Silverman ED, et al. J Pediatr 1983;103:872. Hadchouel M, Prieur AM, and Griscelli C. J Pediatr 1985;106:561.
  16. 16. MAS in Pediatric Rheumatology • Has been reported in association with almost any rheumatic disease • By far, most common in systemic JIA • About 80% of reported cases occurred in association with systemic JIA • SLE, Kawasaki disease • Prevalence of “overt MAS” in systemic JIA is ~10% Sawney, et al. Arch Dis Child 2001;85:4210 • Evidence of subclinical MAS in a subgroup of systemic JIA patients with active systemic disease (~30%) Bleesing, et al. Arthritis Rheum 2007;56:965 Behrens, et al. J Rheumatol 2007:34:1133
  17. 17. Laboratory monitoring for signs of MAS • Cell blood count • Ferritin • Liver enzymes • Fibrinogen • Soluble IL2Rα • Soluble CD163
  18. 18. MΦ MAS mechanisms 21 CD8+ IFN-γ GM-CSF MΦ MΦ MΦ MΦ MΦMΦ MΦ Mo TNF-α IL-6 IL-1 IL-18 M-CSF sCD163 sIL-2Rα CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ CD8+ MΦ CD8+ CD8+
  19. 19. Established Treatments of MAS • High dose corticosteroids • Cyclosporine A • Anakinra in some patients • Etoposide in most difficult cases
  20. 20. Treatments under investigation • Biologics neutralizing INF-gamma (anti-IFN γ antibodies) • Biologics neutralizing IL-18 (recombinant IL18BP) • Jak-Stat inhibitors

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