Are Macrophage Activation Syndrome (MAS) and Hemophagocytic Lymphohistiocytosis (HLH) the same condition?

Are MAS and HLH the Same Condition?

No, Macrophage Activation Syndrome (MAS) and Hemophagocytic Lymphohistiocytosis (HLH) are not the same—MAS is a specific subtype of secondary HLH that occurs exclusively in patients with underlying autoimmune or autoinflammatory diseases. 1

Key Conceptual Framework

MAS represents a distinct entity within the broader HLH spectrum, not a separate condition. 1 The relationship can be understood as follows:

• MAS is secondary HLH with a specific trigger: MAS arises specifically on a background of systemic autoimmunity/autoinflammation, making it a distinct entity within the HLH spectrum according to the American Society of Hematology. 1

• The term MAS should be restricted to patients with Still's disease, systemic lupus erythematosus, vasculitis, and other related autoimmune systemic diseases. 1

• Both conditions share the same pathophysiology: uncontrolled immune activation resulting from hyperactivation of macrophages and lymphocytes, increased production of proinflammatory cytokines, infiltration of lymphocytes and histiocytes in tissues and organs, and immune-mediated multiorgan failure. 2

Why the Distinction Matters Clinically

Treatment Approaches Differ Significantly

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

• MAS first-line treatment: High-dose corticosteroids (methylprednisolone 1g/day IV for 3-5 consecutive days) with second-line options including cyclosporine A, anakinra (IL-1 inhibitor), and tocilizumab (IL-6 inhibitor). 1

• Other secondary HLH treatment: May require more aggressive immunosuppression with etoposide-containing regimens, particularly when triggered by malignancies or severe infections. 1

Diagnostic Biomarkers Can Differentiate

• Free IL-18 levels are significantly higher in MAS associated with Still's disease compared to other HLH forms. 1

• 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. 1

Clinical Overlap and Diagnostic Challenges

Shared Clinical Features

Both conditions present with remarkably similar features, making diagnosis challenging:

• Fever: Nearly universal, characterized by high, persistent, unremitting fever. 3
• Cytopenias: Affecting two or more cell lines (anemia, thrombocytopenia, neutropenia). 3
• Hyperferritinemia: Rapidly rising ferritin >5000 ng/mL is highly suggestive. 3
• Multiorgan dysfunction: Including hepatitis, coagulopathy with hypofibrinogenemia, pulmonary edema, and renal dysfunction. 3
• Elevated inflammatory markers: Including CRP, IL-6, INF-γ, and sIL-2Ra. 2, 3

Important Caveat

In the CAR T-cell therapy setting, the NCCN guidelines note that HLH/MAS symptoms often resolve with clinical management of cytokine release syndrome (CRS), and therefore HLH/MAS was excluded from the definition of CRS due to the degree of similarity. 2 This represents a specific context where the distinction becomes less clinically relevant.

Practical Clinical Algorithm

When to Suspect MAS vs Other HLH

1. Check for underlying autoimmune disease: If the patient has Still's disease, SLE, vasculitis, or other systemic autoimmune conditions → consider MAS. 1

2. Identify the trigger:

   • Autoimmune flare → MAS 1
   • Malignancy (especially T-cell/NK-cell lymphomas) → malignancy-associated HLH 3
   • Infection (especially EBV) → infection-triggered HLH 3
   • CAR T-cell therapy → CAR T-cell-induced HLH 2

3. Consider biomarkers if available: Free IL-18 and S100A12 can help differentiate MAS from other HLH forms. 1

Treatment Initiation

Do not delay empirical treatment while waiting for all HLH-2004 criteria to be met or while determining the exact subtype. 3

• For suspected MAS: Start high-dose methylprednisolone 1g/day IV for 3-5 days, add cyclosporine A if inadequate response within 24-48 hours. 4

• For malignancy-associated or refractory cases: Consider etoposide-containing regimens, though this carries significant toxicity. 1, 3

• Simultaneously treat the underlying trigger: Antimicrobials for infection, chemotherapy for malignancy, disease-modifying therapy for autoimmune conditions. 3

Common Pitfalls to Avoid

• Do not assume they are completely separate diseases: MAS is part of the HLH spectrum, not a distinct entity. 1, 5

• Do not delay treatment while trying to definitively classify the subtype—early recognition and treatment are critical to prevent irreversible organ damage and death. 1, 3

• Do not overlook the underlying trigger: Treating the hyperinflammation without addressing the underlying autoimmune disease, infection, or malignancy will lead to treatment failure. 3

• Do not apply pediatric HLH protocols directly to adults: Dose adjustments and different considerations are required. 3