About MAS

MAS: A hyperinflammatory syndrome with devastating effects in rheumatic diseases^1-3

Macrophage activation syndrome (MAS) is a subtype of hemophagocytic lymphohistiocytosis (HLH). MAS is the term used for HLH that  is associated with underlying rheumatic diseases.¹

MAS in Still's disease is estimated to occur in up to:

15%

of adults with adult-onset Still's disease (AOSD)^2,4

AND

10%

of patients with systemic juvenile idiopathic arthritis (sJIA)^2,4

MAS is characterized by:

Interferon gamma (IFNγ)-hyperactivated macrophages that release an uncontrolled surge of proinflammatory cytokines sometimes referred to as the "cytokine storm."⁵

Systemic, life-threatening hyperinflammation that can result in organ damage.²

What influences when HLH/MAS becomes clinically apparent?

The threshold model of HLH is a framework for viewing the disease as a biological continuum. The model can be used to reflect various combinations of genetic susceptibility* and hyperinflammatory contributors.^6,7

Threshold Model of Hemophagocytic Lymphohistiocytosis (HLH)

*Note that the genetic susceptibility that drives HLH/MAS can include innate and somatic genetic mutations.^6,8

As a subtype, HLH/MAS can be visualized by placing examples along the continuum, based on individual patient presentation.⁷

Threshold model legend: infection, background inflammation, and innate genetic mutations.

HLH Threshold - Macrophage Activation Syndrome (MAS) Example 1

HLH Threshold - Macrophage Activation Syndrome (MAS) Example 2

HLH Threshold - Macrophage Activation Syndrome (MAS) Example 3

MAS Example #1

Genetic predisposition + inflammation from underlying condition (sJIA/AOSD) + infection pushes over threshold.

MAS Example #2

Inflammation from underlying condition (sJIA/AOSD) + infection pushes over threshold. There is no known genetic predisposition.

MAS Example #3

Genetic predisposition + inflammation from underlying condition (sJIA/AOSD) pushes over threshold. There is no evidence of infection.

The clinical presentation of MAS can overlap with^2,3,9-13:

Malignancy
Liver failure
Infections, including sepsis
Immune disorders

Anemia
Kawasaki disease
Flares of rheumatic disease, including AOSD, sJIA, and lupus
Thrombotic microangiopathy (TMA)

Subclinical MAS

30% to 40% of patients with sJIA may experience subclinical MAS during disease flares, which can develop into fulminant MAS. Patients with subclinical MAS may exhibit more subtle abnormalities without overt clinical symptoms.^2,14

MAS signs and symptoms

In patients with MAS, uncontrolled levels of proinflammatory cytokines overwhelm multiple organ systems. This may initially present as general malaise in early stages but can quickly progress to widespread damage.^1,15,16 More specific signs and symptoms include^9,10,16,†:

Persistent/unremitting fever of unknown origin
Hyperferritinemia
Hypertriglyceridemia
Liver dysfunction
Lymphadenopathy

Cytopenias (anemia, thrombocytopenia, and neutropenia)
Coagulopathies (easy bruising or bleeding, petechial or purpuric rash)
Central nervous system (CNS) involvement
Hemophagocytosis

Unresolved MAS may progress to multiple organ failure and is associated with mortality rates up to 39%.³

^†This is not an exhaustive list of MAS signs and symptoms. Presentation may vary between patients, and it is not necessary to identify all of these symptoms to diagnose MAS.

Recognize the pattern

A pattern of common clinical and laboratory findings can raise suspicion⁷:

FEVER

FERRITIN

FALLING BLOOD COUNTS

Consider these findings together and in the context of the patient's clinical presentation when evaluating for MAS.⁷

Explore how MAS is diagnosed

References

Sen ES, Clarke SLN, Ramanan AV. Macrophage activation syndrome. Indian J Pediatr. 2016;83(3):248-253. doi:10.1007/s12098-015-1877-1
Ravelli A, Minoia F, Davì S, et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2016;68(3):566-576. doi:10.1002/art.39332
Carter SJ, Tattersall RS, Ramanan AV. Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology (Oxford). 2019;58(1):5-17. doi:10.1093/rheumatology/key006
Giacomelli R, Ruscitti P, Shoenfeld Y. A comprehensive review on adult-onset Still's disease. J Autoimmun. 2018;93:24-36. doi:10.1016/j.jaut.2018.07.018
Schulert GS, Grom AA. Macrophage activation syndrome and cytokine directed therapies. Best Pract Res Clin Rheumatol. 2014;28(2):277-292. doi:10.1016/j.berh.2014.03.002
Steen EA, Hermiston ML, Nichols KE, Meyer LK. Digenic inheritance: evidence and gaps in hemophagocytic lymphohistiocytosis. Front Immunol. 2021;12:777851. doi:10.3389/fimmu.2021.777851
Henter JI. Hemophagocytic lymphohistiocytosis. N Engl J Med. 2025;392(6):584-598. doi:10.1056/NEJMra2314005
Miller PG, Sperling AS, Gibson CJ, et al. Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis. Blood. 2020;136(26):3051-3055. doi:10.1182/blood.2020008206
Bseiso O, Zahdeh A, Isayed O, Mahagna S, Bseiso A. The role of immune mechanisms, inflammatory pathways, and macrophage activation syndrome in the pathogenesis of hemophagocytic lymphohistiocytosis. Cureus. 2022;14(12):e33175. doi:10.7759/cureus.33175
Lerkvaleekul B, Vilaiyuk S. Macrophage activation syndrome: early diagnosis is key. Open Access Rheumatol. 2018;10:117-128. doi:10.2147/OARRR.S151013
Ishii E. Hemophagocytic lymphohistiocytosis in children: pathogenesis and treatment. Front Pediatr. 2016;4:47. doi:10.3389/fped.2016.00047
Kumar S, Vaidyanathan B, Gayathri S, Rajam L. Systemic onset juvenile idiopathic arthritis with macrophage activation syndrome misdiagnosed as Kawasaki disease: case report and literature review. Rheumatol Int. 2013;33(4):1065-1069. doi:10.1007/s00296-010-1650-8
Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Arthritis Rheumatol. 2023;75(10):1714-1732. doi:10.1002/art.42636
Behrens EM, Beukelman T, Paessler M, Cron RQ. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol. 2007;34(5):1133-1138
Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing and treating hemophagocytic syndromes. Pediatr Clin North Am. 2012;59(2):329-344. doi:10.1016/j.pcl.2012.03.002
Crayne C, Cron RQ. Pediatric macrophage activation syndrome, recognizing the tip of the iceberg. Eur J Rheumatol. 2020;7(Suppl1):S13-S20. doi:10.5152/eurjrheum.2019.19150

MAS: A hyperinflammatory syndrome with devastating effects in rheumatic diseases^1-3

MAS in Still's disease is estimated to occur in up to:

MAS is characterized by:

What influences when HLH/MAS becomes clinically apparent?

The clinical presentation of MAS can overlap with^2,3,9-13:

Subclinical MAS

MAS signs and symptoms

Recognize the pattern

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

MAS: A hyperinflammatory syndrome with devastating effects in rheumatic diseases1-3

MAS in Still's disease is estimated to occur in up to:

MAS is characterized by:

What influences when HLH/MAS becomes clinically apparent?

The clinical presentation of MAS can overlap with2,3,9-13:

Subclinical MAS

MAS signs and symptoms

Recognize the pattern

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

MAS: A hyperinflammatory syndrome with devastating effects in rheumatic diseases^1-3

The clinical presentation of MAS can overlap with^2,3,9-13: