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Macrophage activation syndrome
A severe inflammatory condition often seen in autoimmune diseases.
Overview
Macrophage activation syndrome (MAS) is a rare but potentially life-threatening condition characterized by excessive activation and proliferation of macrophages and T lymphocytes, leading to a severe inflammatory response. It is considered a form of secondary hemophagocytic lymphohistiocytosis (HLH) and is most commonly seen in association with systemic juvenile idiopathic arthritis (sJIA), systemic lupus erythematosus (SLE), and other autoimmune or autoinflammatory diseases. MAS results in overwhelming cytokine production, multi-organ dysfunction, and hemophagocytosis—where immune cells begin to engulf healthy blood cells.
The syndrome requires immediate recognition and treatment due to its rapid progression and high mortality risk if left untreated. It is a medical emergency that often presents in pediatric populations but can also occur in adults with rheumatic diseases.
Causes
Macrophage activation syndrome is typically triggered by an immune system dysregulation in response to underlying disease or an external factor. Common causes include:
Systemic juvenile idiopathic arthritis (sJIA): The most frequent rheumatic trigger in children.
Systemic lupus erythematosus (SLE): More common in adolescents and adults.
Infections: Viral (e.g., Epstein-Barr virus, cytomegalovirus), bacterial, or fungal infections can trigger MAS.
Medications: Some immunosuppressive or anti-inflammatory drugs may contribute to onset in susceptible individuals.
Malignancies: Especially lymphomas or leukemias, as part of secondary HLH spectrum.
The hallmark of MAS is uncontrolled activation of immune cells that release large quantities of pro-inflammatory cytokines, resulting in a "cytokine storm" that causes tissue damage and systemic symptoms.
Symptoms
The clinical presentation of MAS can mimic severe sepsis or flare-ups of underlying autoimmune conditions. Common symptoms and signs include:
Persistent high fever that does not respond to antibiotics or antipyretics.
Enlarged liver and spleen (hepatosplenomegaly).
Lymphadenopathy: Swollen lymph nodes.
Severe fatigue and malaise.
Skin rash or mucosal bleeding.
Neurological symptoms: Confusion, seizures, or altered mental status in severe cases.
Low blood cell counts: Anemia, leukopenia, and thrombocytopenia.
Elevated liver enzymes and coagulopathy: Indicating liver dysfunction and risk of bleeding.
Laboratory findings often reveal hyperferritinemia (very high ferritin levels), elevated triglycerides, low fibrinogen, and increased levels of liver enzymes and D-dimer.
Diagnosis
Diagnosis of MAS is complex and requires a high index of suspicion, particularly in patients with known autoimmune diseases who develop acute, unexplained systemic symptoms. Diagnostic steps include:
Clinical assessment: Recognizing the pattern of fever, cytopenias, and organ dysfunction.
Laboratory tests:
Ferritin: Usually extremely elevated (>5000 ng/mL in many cases).
Triglycerides: Often elevated.
Fibrinogen: Usually decreased.
Liver enzymes: ALT and AST typically elevated.
Complete blood count (CBC): Shows pancytopenia.
Bone marrow biopsy: May reveal hemophagocytosis—macrophages engulfing other blood cells.
HLH-2004 criteria: Sometimes used for classification, though MAS-specific diagnostic guidelines like the 2016 MAS criteria for sJIA are more appropriate in rheumatologic contexts.
MAS must be differentiated from sepsis, flares of underlying rheumatic disease, and other causes of organ failure or cytopenias.
Treatment
MAS is a medical emergency that requires prompt and aggressive treatment. The therapeutic approach typically includes:
High-dose corticosteroids: First-line treatment to control inflammation and immune activation.
Cyclosporine A: Often added for steroid-resistant or severe cases.
Anakinra (IL-1 receptor antagonist): Particularly effective in MAS associated with sJIA.
IVIG (Intravenous immunoglobulin): Used in some cases, especially in infection-triggered MAS.
Supportive care: Includes blood transfusions, liver support, and management of coagulation disorders.
Treatment of underlying cause: Whether it be autoimmune disease, infection, or malignancy.
In refractory or fulminant cases, other immunosuppressive agents such as etoposide or tocilizumab (anti-IL-6) may be considered under expert supervision.
Prognosis
The prognosis of MAS largely depends on early recognition and timely initiation of appropriate treatment. When identified and treated promptly, many patients recover completely. However, delays in diagnosis or inadequate management can lead to multi-organ failure and death.
Prognostic factors include:
Severity of cytokine storm and organ involvement.
Underlying disease activity (e.g., uncontrolled lupus or JIA).
Response to initial therapy - early responders typically have better outcomes.
Regular monitoring and long-term management of the underlying autoimmune or autoinflammatory condition are essential to reduce the risk of recurrence. Continued research into MAS has improved understanding and therapeutic approaches, but vigilance remains key to improving survival and outcomes.
Medical Disclaimer
The information provided on this page is for educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.