What is MAS?

MAS and HLH

Macrophage activation syndrome (MAS) is a subtype of hemophagocytic lymphohistiocytosis (HLH) that occurs as a complication of rheumatic disease, most frequently in patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD).1

MAS is estimated to occur in up to:

15%

of adults with AOSD2

MAS is estimated to occur in up to:

10%

of children with sJIA3

Similar to other forms of HLH, MAS is caused by expansion of T lymphocytes and activation of macrophages resulting in hyperinflammation.4

Signs and symptoms of MAS

Features of MAS include3,5:
Persistent fever
Hyperferritinemia
Cytopenia
Liver dysfunction
Hepatosplenomegaly
Coagulopathies
Hemophagocytosis*
Hypofibrinogenemia
Lymphadenopathy
CNS dysfunction
Elevated sCD25
Elevated CXCL9

*Note that hemophagocytosis is not specific nor always present in early stages of the disease.

10%-20% mortality rate has been observed in patients with unresolved MAS due to multiorgan failure6,7

Identifying MAS in patients

MAS can closely resemble sepsis or disease flares, so it’s crucial to be mindful of its potential for development in patients with underlying rheumatic disease and patients in whom rheumatic disease has not yet been identified. Data from a single-center study conducted among 118 adult MAS patients suggest that approximately one-third of patients may present with MAS before receiving a rheumatic disease diagnosis.1,8

The European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) have codeveloped classification criteria for identifying MAS in patients with sJIA.3

A febrile patient with known or suspected sJIA is classified as having MAS if they have3:

Ferritin levels >684 ng/mL and any 2 of the following lab abnormalities:
Platelet count ≤181 x 109/L
Aspartate aminotransferase >48 U/L
Triglycerides >156 mg/dL
Fibrinogen ≤360 mg/dL

Some biomarkers of inflammation can measure key disease pathways, and their specificity may be helpful for identifying MAS. These include5:

Potential biomarkers to monitor in MAS
sCD25
IL-18
CXCL9
Neopterin
CD163

CD163=cluster of differentiation 163; CXCL9=chemokine (C-X-C motif) ligand 9; IL=interleukin; sCD25=soluble interleukin-2 receptor.

While these assessments may help to identify MAS, currently there is no single set of criteria that has been validated for diagnosing MAS across all contexts.7

There is also a risk that patients may experience recurrent MAS episodes. However, there is limited information about biomarkers or clinical factors that can predict this in patients.9 It is important to remain vigilant when evaluating patients at risk of developing MAS and be prepared to act.

Subclinical MAS

It’s important to consider that treatment for underlying rheumatic disease may mask the symptoms of MAS.10

Subclinical MAS is more difficult to detect due to the absence of fever and/or lower levels of ferritin, C-reactive protein, and triglycerides. In these cases, some patients receiving treatment for their rheumatic disease may experience fewer symptoms and have less prominent laboratory changes compared to patients who are not currently on treatment.10,11

~40% of children with sJIA may develop subclinical MAS.6

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References: 1. Sen ES, Clarke SL, Ramanan AV. Macrophage activation syndrome. Indian J Pediatr. 2016;83(3):248-253. doi:10.1007/s12098-015-1877-1 2. 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 3. 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 4. De Matteis A, Colucci M, Rossi MN, et al. Expansion of CD4dimCD8+ T cells characterizes macrophage activation syndrome and other secondary HLH. Blood. 2022;140(3):262-273. doi:10.1182/blood.2021013549 5. 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 6. De Benedetti F, Grom AA, Brogan PA, et al. Ann Rheum Dis. 2023;82(6):857-865. doi:10.1136/ard-2022-223739 7. Wang R, Li T, Ye S, et al. Macrophage activation syndrome associated with adult-onset Still’s disease: a multicenter retrospective analysis. Clin Rheumatol. 2020;39(8):2379-2386. doi:10.1007/s10067-020-04949-0 8. He L, Yao S, Zhang R, et al. Macrophage activation syndrome in adults: characteristics, outcomes, and therapeutic effectiveness of etoposide-based regimen. Front Immunol. 2022;13:955523. doi:10.3389/fimmu.2022.955523 9. Erkens R, Esteban Y, Towe C, Schulert G, Vastert S. Pathogenesis and treatment of refractory disease courses in systemic juvenile idiopathic arthritis: refractory arthritis, recurrent macrophage activation syndrome and chronic lung disease. Rheum Dis Clin North Am. 2021;47(4):585-606. doi:10.1016/j.rdc.2021.06.003 10. Lerkvaleekul B, Vilaiyuk S. Macrophage activation syndrome: early diagnosis is key. Open Access Rheumatol. 2018;10:117-128. doi:10.2147/OARRR.S151013 11. Ng S, Talbot J, Clinch J, Ohlsson V, Rogers V. O15 recognition of subclinical macrophage activation syndrome in an adolescent systemic juvenile idiopathic arthritis patient receiving tocilizumab: a case report Rheumatol Adv Pract. 2020;4(suppl 1):rkaa054.003. doi:10.1093/rap/rkaa054.003