From the Guidelines
The principal cytokines involved in macrophage activation syndrome (MAS) are interferon-gamma (IFN-γ), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-18 (IL-18), and tumor necrosis factor-alpha (TNF-α). These cytokines create a cytokine storm that drives the pathophysiology of MAS. IFN-γ is considered the most critical cytokine in MAS development, as it directly activates macrophages and promotes their uncontrolled proliferation and activation. IL-18 works synergistically with IFN-γ to enhance macrophage activation, while IL-1 and IL-6 contribute to the inflammatory cascade and systemic manifestations. TNF-α further amplifies the inflammatory response and tissue damage. The hyperactivation of these cytokines leads to the characteristic features of MAS, including hemophagocytosis, hyperferritinemia, coagulopathy, and multi-organ dysfunction. Understanding these cytokine pathways has led to targeted therapies for MAS, including IL-1 inhibitors (anakinra, canakinumab), IL-6 inhibitors (tocilizumab), and in some cases, therapies targeting IFN-γ (emapalumab) for refractory cases 1.
Key Cytokines Involved in MAS
- Interferon-gamma (IFN-γ)
- Interleukin-1 (IL-1)
- Interleukin-6 (IL-6)
- Interleukin-18 (IL-18)
- Tumor necrosis factor-alpha (TNF-α)
Pathophysiology of MAS
The cytokine storm driven by these cytokines leads to the activation of macrophages, which in turn causes hemophagocytosis, hyperferritinemia, coagulopathy, and multi-organ dysfunction. The understanding of this pathophysiology has led to the development of targeted therapies for MAS.
Targeted Therapies for MAS
- IL-1 inhibitors (anakinra, canakinumab)
- IL-6 inhibitors (tocilizumab)
- Therapies targeting IFN-γ (emapalumab) for refractory cases
The most recent and highest quality study, published in 2024, provides evidence for the efficacy of these targeted therapies in treating MAS 1. The study suggests that early initiation of IL-1 or IL-6 inhibitors leads to high levels of rapid GC-free clinical inactive disease (CID) and that these therapies should be initiated as soon as the diagnosis of Still's disease is made. Additionally, the study highlights the importance of monitoring patients with Still's disease for the development of MAS and the need for targeted therapies in patients who fail to respond to high-dose glucocorticoids.
From the Research
Principal Cytokines Involved in Macrophage Activation Syndrome (MAS)
The principal cytokines involved in MAS include:
- Interleukin (IL)-1 2, 3
- IL-6 2, 4, 3, 5
- IL-18 2, 4, 3, 5
- Interferon (IFN)-γ 2, 4, 3, 5
- Tumor necrosis factor (TNF)-α 2, 3, 5
- Soluble TNF receptor (sTNFR) type I and type II 5
Cytokine Storm and MAS Pathogenesis
A cytokine storm with elevated pro-inflammatory cytokines is central to the pathogenesis of MAS 2, 4, 3. This storm results in the activation of macrophages, causing hemophagocytosis and contributing to multi-organ dysfunction 3.
Diagnostic Markers for MAS
Serum levels of certain cytokines, such as sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA, might be useful diagnostic markers for the transition from active phase to MAS 5.