What is the key difference between Macrophage Activation Syndrome (MAS) and Hemophagocytic Lymphohistiocytosis (HLH)?

Key Difference Between MAS and HLH

MAS is a specific subtype of secondary HLH that occurs exclusively in patients with underlying autoimmune or autoinflammatory diseases (such as Still's disease, lupus, or vasculitis), while HLH is the broader umbrella term that encompasses both primary (genetic) and secondary forms triggered by infections, malignancies, or autoimmune conditions. 1

Pathogenetic Distinction

MAS and HLH share a common terminal pathway of hyperinflammation but have fundamentally different pathogenetic roots. 1

• MAS arises specifically on a background of systemic autoimmunity/autoinflammation, making it a distinct entity within the HLH spectrum 1
• Other forms of secondary HLH are triggered by infections (most common), malignancies (particularly T-cell and NK-cell lymphomas), or iatrogenic causes 1, 2
• The term MAS should be restricted to patients with Still's disease, lupus, vasculitis, and other related autoimmune systemic diseases 1

Clinical and Laboratory Differences

While both conditions present with hyperferritinemia and hyperinflammation, there are distinguishing features:

Laboratory Parameters

• Soluble IL-2R levels are significantly lower in MAS (median 6814.5 kU/L) compared to malignancy-associated HLH (median 27,972 kU/L), representing a four-fold difference 3
• Platelet counts are nearly double in MAS patients (median 50.0 K/µL) versus malignancy-associated HLH (median 29.0 K/µL) 3
• Free IL-18 levels are significantly higher in MAS associated with Still's disease compared to other HLH forms 4
• S100A12 can differentiate MAS from both primary and secondary HLH with high sensitivity and specificity, particularly helpful when MAS presents before the underlying autoimmune diagnosis is clear 4

Clinical Features

• Hepatomegaly is absent in MAS but present in 25% of malignancy-associated HLH cases 3

Treatment Implications: The Critical Distinction

The treatment approach differs significantly between MAS and other forms of secondary HLH, which is why the distinction matters clinically. 1

MAS Treatment Strategy

• First-line: High-dose corticosteroids (methylprednisolone 1g/day IV for 3-5 consecutive days) 4, 2
• Second-line options include:
  • Cyclosporine A 4, 2
  • Anakinra (IL-1 inhibitor) 4, 2
  • Tocilizumab (IL-6 inhibitor) 4, 2
• These agents specifically target the autoimmune/autoinflammatory pathways underlying MAS 4

Other Secondary HLH Treatment Strategy

• May require more aggressive immunosuppression with etoposide-containing regimens, particularly when triggered by malignancies or severe infections 4, 2
• Etoposide per HLH-94 protocol combined with high-dose corticosteroids for cases with imminent organ failure 5
• Rituximab for EBV-triggered HLH 2
• Antimicrobials for infection-triggered HLH 2
• Chemotherapy for malignancy-associated HLH 2

Common Pitfalls to Avoid

• Do not use the term MAS for infection- or malignancy-triggered secondary HLH—this terminology should be reserved exclusively for HLH in the context of autoimmune/autoinflammatory diseases 4
• Do not delay empirical treatment while waiting to differentiate MAS from other HLH forms—both can progress rapidly to multiorgan failure and death 1, 2
• Do not overlook the underlying autoimmune disease in MAS patients—treating the trigger is essential alongside treating the hyperinflammation 2
• Do not apply the same treatment protocol to all HLH patients—MAS typically responds better to corticosteroids and targeted immunomodulators, while malignancy-associated HLH may require etoposide 4, 2

Prognostic Differences

• MAS patients have better overall mortality (22%) compared to malignancy-associated HLH (44%), though this difference did not reach statistical significance in one retrospective study 3
• Early recognition of the underlying trigger is critical for both conditions to prevent irreversible organ damage and death 1