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

Difference Between HLH and MAS

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

Conceptual Framework

MAS and HLH share a common terminal pathway of hyperinflammation but have different pathogenetic roots. 1 Both are hyperferritinemic hyperinflammatory syndromes driven by aberrantly activated T cells and macrophages, resulting in a potentially fatal cytokine storm. 1

Key Distinguishing Features:

Underlying Disease Context:

• MAS (also termed MAS-HLH) specifically refers to HLH arising on a background of systemic autoimmune/autoinflammatory diseases, and the term should be restricted to patients with Still's disease (systemic juvenile idiopathic arthritis/adult-onset Still's disease), systemic lupus erythematosus, vasculitis, and other related autoimmune systemic diseases. 1
• HLH is the broader category that includes primary (genetic) forms caused by mutations affecting lymphocyte cytotoxicity, and secondary forms triggered by infections, malignancies, or autoimmune disorders. 1

Age Distribution:

• Primary HLH is most common in children but can occur in adolescents and young adults. 1
• Secondary HLH (including MAS) is most frequent in adults, with a mean age at onset of 49 years. 1

Diagnostic Biomarker Differences

Novel biomarkers can help differentiate MAS from other forms of HLH:

• IL-18 levels: Free IL-18 levels are significantly higher in MAS associated with Still's disease compared to other forms of HLH, though IL-18BP levels do not differ between MAS and other HLH forms. 1
• S100A12: Can differentiate MAS from both primary and secondary HLH with high sensitivity and specificity, particularly helpful when MAS presents at disease onset before the underlying autoimmune diagnosis is clear. 1
• Activated CD8 T cells: While markedly elevated CD38high/HLA-DR+CD8+ T cells can differentiate MAS from active Still's disease, these populations are similarly increased in all forms of secondary HLH, meaning they do not differentiate MAS from other secondary HLH subtypes. 1

Treatment Implications

The distinction matters because treatment approaches may differ:

• MAS treatment typically starts with high-dose corticosteroids as first-line therapy, with second-line options including cyclosporine A, anakinra, or tocilizumab—agents specifically targeting the autoimmune/autoinflammatory pathways. 1, 2
• Other secondary HLH forms may require more aggressive immunosuppression with etoposide-containing regimens, particularly when triggered by malignancies or severe infections. 1, 2
• Corticosteroids and/or IVIG may be sufficient as first-line therapy for patients with underlying rheumatologic disease presenting with MAS, whereas viral/infection-associated HLH more frequently requires etoposide. 3

Genetic Overlap

The distinction between primary and secondary HLH/MAS is increasingly blurred by genetic findings:

• Heterozygous mutations in perforin-pathway genes have been found in MAS patients, potentially functioning as hypomorphic or partial dominant-negative alleles that contribute to disease pathogenesis. 4
• This suggests a threshold model where genetic predisposition combines with chronic inflammation and/or infections to trigger MAS pathology. 4

Clinical Pitfalls to Avoid

• Do not use HLH-2004 diagnostic criteria rigidly for MAS: These criteria were developed for previously non-activated immune systems and do not perform well in MAS, where baseline immune activation (e.g., thrombocytosis and elevated fibrinogen in Still's disease) alters expected laboratory values. 5
• Do not assume all secondary HLH is MAS: The term MAS should be reserved specifically for HLH in the context of autoimmune/autoinflammatory diseases, not for infection- or malignancy-triggered secondary HLH. 1
• Do not overlook co-triggers: Patients with autoimmune disease may have both MAS and concurrent infection (e.g., EBV viremia), requiring treatment of both the autoimmune trigger and the infectious trigger. 6