Macrophage Activation Syndrome in SJIA

Alexei Grom, MD

Cincinnati Children’s Hospital Medical Center

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

Normal macrophages

• a type of white blood cells that engulfs and destroys microbes and other foreign substances in a process called phagocytosis

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

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)

Annual Reviews

MAS is a cytokine storm

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

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Proposed Mechanisms of Macrophage Activation in Hemophagocytic Syndromes

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CD8+

IFN-γ

GM-CSF

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MΦ

MΦMΦ

MΦMΦ

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Mo

TNF-α

IL-6

IL-1

IL-18

M-CSF

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

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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

Annual Reviews

MΦ

Proposed Mechanisms of Macrophage Activation in Hemophagocytic Syndromes

14

CD8+

IFN-γ

GM-CSF

MΦ

MΦ

MΦMΦ

MΦMΦ

MΦ

Mo

TNF-α

IL-6

IL-1

IL-18

M-CSF

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

CD8+

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CD8+

CD8+

Cytolytic Defects in FHLHCytolytic cells cause destruction of target cells by delivering granules that contain proteins such as perforin and granzymes

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death

Infected Cell

Effector Cell (NK Cell)

Granzyme B

Fusion

Priming

Munc13-4

Munc18-2

Syntaxin 11

Rab27a

Nucleus

Perforin

Signs and Symptoms Macrophage Activation Syndrome

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.

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;56:965Behrens, et al. J Rheumatol 2007:34:1133

Laboratory monitoring for signs of MAS

• Cell blood count

• Ferritin

• Liver enzymes

• Fibrinogen

• Soluble IL2Rα

• Soluble CD163

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MAS mechanisms

21

CD8+

IFN-γ

GM-CSF

MΦ

MΦ

MΦMΦ

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+

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CD8+

CD8+

Established Treatments of MAS

• High dose corticosteroids

• Cyclosporine A

• Anakinra in some patients

• Etoposide in most difficult cases

Treatments under investigation

• Biologics neutralizing INF-gamma (anti-IFN γ antibodies)

• Biologics neutralizing IL-18 (recombinant IL18BP)

• Jak-Stat inhibitors