When to Consider IVIG for Macrophage Activation Syndrome (MAS): Key Insights, Based on the Latest Evidence

静脉注射免疫球蛋白 (IVIG) for macrophage activation syndrome (MAS) may be an option when patients cannot use other immunosuppressive medications. Discover how IVIG works, learn about its potential benefits, and find answers to your most common questions.

亮点

• Macrophage activation syndrome (MAS) is a rare but potentially life-threatening immune response. 
• IVIG for macrophage activation syndrome may serve as a first- or second-line treatment, depending on the underlying trigger, the patient’s response to other medications, and the stage of macrophage activation. 
• IVIG is usually preferred when a patient is moderately ill and has an underlying infection. 
• How IVIG works for MAS is unclear. However, it is thought to work by suppressing macrophage activation and promoting the release of anti-inflammatory molecules. 
• Large, controlled trials are needed to confirm clear benefits and dosage ranges. 

A Quick Overview of Macrophage Activation Syndrome (MAS)

MAS is a rare but potentially fatal immune response to rheumatic disorders, cancers, infections, or medications. It occurs when your immune system floods the body with certain types of white blood cells called macrophages and T cells. 

Normally, these cells help destroy disease-causing microorganisms and cancer cells. However, in MAS, these white blood cells become ineffective. As a result, the immune system produces more of these cells, potentially leading to failure of organ systems or death. 

Studies show death may occur in 20% to 53% of cases [1].

What causes the immune system to overreact is not fully understood, and many cases occur without any identifiable triggers. Infections are thought to trigger nearly 50% of MAS cases. Additionally, 10% of children with systemic juvenile idiopathic arthritis develop full-blown MAS [2].

Other triggers can include:

• Rheumatic disorders, such as Kawasaki Disease and juvenile 系统性红斑狼疮
• Medications, such as aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs)
• Disease flares (worsening of symptoms of a chronic disease, especially 自身免疫性疾病)

The signs and symptoms of MAS can include:

• 肝脏和脾脏肿大
• Worsening liver function
• Swollen lymph glands
• Constantly high fever
• Seizures and coma
• 贫血（红细胞计数低）
• 震惊
• 皮疹

Treatment of Macrophage Activation Syndrome 

There is no consensus about specific treatment for MAS. 

Before biologics came into existence, IVIG, glucocorticoids, and cyclosporine were widely used to treat rheumatic disease-associated MAS. Currently, these medications are used alone or in combination with biologic agents [3].

IVIG for Macrophage Activation Syndrome: What We Know So Far

IVIG may benefit some patients with MAS, especially when administered early. However, success and efficacy vary widely, and studies have found mixed results. 

For example, in a 2001 study, IVIG produced partial or delayed improvement in five patients but no effects in another five patients. The total number of participants in the study was 20. 

The researchers concluded that IVIG for macrophage activation syndrome might be an option when started during the early stages of macrophage activation [4].

IVIG can be a first-line treatment for patients with chronic granulomatous disease (CGD) complicated by macrophage activation syndrome [5]. 

Researchers from a 2020 case report revealed that IVIG may be [6]:

• First-line treatment for systemic lupus erythematosus (SLE) with macrophage activation syndrome.
• Second-line treatment with intravenous steroids. 

Likewise, according to the 2022 EULAR/American College of Rheumatology consensus statements, high-dose glucocorticoids, anakinra with or without IVIG, could be the initial treatment for people with rapidly progressive MAS [7]. 

Available evidence suggests that the effectiveness of IVIG for macrophage activation syndrome is case-dependent. 

For example, IVIG appears to be less effective in severe or refractory cases. However, IVIG therapy should be considered for patients who are unable to receive immunosuppressive medications. IVIG is usually preferred when a patient is moderately ill and has an underlying infection. 

IVIG for Macrophage Activation Syndrome: Understanding the Mechanism of Action

The exact mechanism of action of IVIG for macrophage activation syndrome is poorly understood. 

IVIG is thought to improve MAS symptoms by [8,9]: 

• Suppressing macrophage activation and release of inflammatory substances.
• Activating macrophages to release large amounts of anti-inflammatory molecules.
• Promoting degradation of inflammation-causing macrophages. 

There is no specific dose, which likely depends on the underlying illness and the patient’s response. For moderately ill patients, the usual dose is 1 g to 2 g/kg/dose IV [3].

常见问题

What are the treatment options for MAS?

Treatment options for MAS are IVIG, glucocorticoids, cyclosporine, plasma exchange, and anakinra. 

What is the difference between MAS and HLH?

Macrophage activation syndrome (MAS) and 噬血细胞性淋巴组织细胞增生症 (HLH) are potentially fatal conditions with overlapping symptoms. Nonetheless, MAS is usually associated with rheumatologic disorders, such as systemic juvenile idiopathic arthritis (sJIA), while HLH is often associated with viral infections, cancers, and certain medications [10].

What is MAS in systemic JIA?

MAS is a potentially fatal complication of systemic juvenile idiopathic arthritis (s-JIA). Studies show that 1 in 10 children with s-JIA develops MAS. 

What is the life expectancy in macrophage activation syndrome (MAS)?

In a 2022 study involving 20 adults with rheumatic disease-associated MAS, overall survival at 3 and 6 months was 75.2% and 64.3%, respectively. During the study period, opportunistic infections affected nine participants, and five of them died [11].

What are the FDA-approved IVIG products for macrophage activation syndrome (MAS)?

The FDA has not yet approved any IVIG product for macrophage activation syndrome (MAS). Currently, IVIG use is off-label. In the U.S., the only FDA-approved treatment for MAS is Gamifant (emapalumab-lzsg), which is an interferon gamma-blocking antibody.