Macrophage activation syndrome is hemophagocytic lymphohistiocytosis associated with juvenile idiopathic arthritis (JIA; particularly systemic JIA) and with several other systemic rheumatic diseases (particularly systemic lupus erythematosus and adult-onset Still disease). Diagnosis is clinical. Treatment involves medications for the underlying rheumatic disease and, in systemic JIA, high-dose corticosteroids.
Macrophage activation syndrome is a severe, overwhelming, and life-threatening cytokine storm syndrome caused by an uncontrolled macrophage and T lymphocyte expansion. It occurs in 10% of children with systemic juvenile idiopathic arthritis (JIA) (1).
General reference
1. Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13(4):289-298. doi:10.1038/gene.2012.3
Symptoms and Signs of Macrophage Activation Syndrome
Features of macrophage activation syndrome include
High, unremitting fever
Hepatosplenomegaly
Generalized lymphadenopathy
Rash
Hemorrhagic manifestations
Central nervous system dysfunction (including seizures and coma)
Shock
Diagnosis of Macrophage Activation Syndrome
History and physical examination
Clinical criteria
The diagnosis of macrophage activation syndrome requires a high index of clinical suspicion, particularly among patients with existing systemic rheumatic diseases such as systemic lupus erythematosus or JIA. Classification criteria have been developed primarily for research purposes but are often used by clinicians to help establish the diagnosis (1).
Macrophage activation syndrome can be difficult to distinguish from active systemic JIA because both conditions share many overlapping clinical features. Features that help distinguish macrophage activation syndrome from systemic JIA include the unremitting fever (unlike the intermittent daily fevers of JIA), constant rash (unlike the transient rash of systemic JIA), hemorrhagic manifestations, seizures, coma, and shock. Despite marked systemic inflammation, the erythrocyte sedimentation rate (ESR) is paradoxically depressed because of low fibrinogen levels.
Classification criteria that help establish the diagnosis of macrophage activation syndrome in patients with JIA include patients with a ferritin level > 684 ng/mL ( > 684 mcg/L) plus any 2 of the following (1):
Platelets ≤ 181,000/mcL (≤ 181 × 109/L)
Aspartate aminotransferase > 48 units/L (> 0.80 microkat/L)
Triglycerides > 156 mg/dL (> 1.76 mmol/L)
Fibrinogen ≤ 360 mg/dL (≤ 10.58 g/L)
Diagnosis reference
1. Ravelli A, Minoia F, Davì 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. Arthritis Rheumatol. 2016;68(3):566-576. doi:10.1002/art.39332
Treatment of Macrophage Activation Syndrome
High-dose corticosteroids
Other immunosuppressive agents
No consensus exists regarding specific treatment.
Macrophage activation syndrome may respond well to successful treatment of the underlying rheumatic disease.
Treatment of this syndrome as a complication of systemic JIA or of systemic lupus erythematosus usually includes high-dose corticosteroids and may include other medications (eg, cyclosporine, interleukin [IL]-1 inhibitors, Janus kinase inhibitors, emapalumab) (Treatment of this syndrome as a complication of systemic JIA or of systemic lupus erythematosus usually includes high-dose corticosteroids and may include other medications (eg, cyclosporine, interleukin [IL]-1 inhibitors, Janus kinase inhibitors, emapalumab) (1).
Treatment reference
1. Baldo F, Erkens RGA, Mizuta M, et al. Current treatment in macrophage activation syndrome worldwide: a systematic literature review to inform the METAPHOR project. Rheumatology (Oxford). Published online July 26, 2024. doi:10.1093/rheumatology/keae391
Prognosis for Macrophage Activation Syndrome
Macrophage activation syndrome has a high mortality rate because of multiorgan failure.
