What happens in MAS?
Macrophage activation syndrome and underlying rheumatic disease
In macrophage activation syndrome (MAS) associated with underlying rheumatic disease, a dysregulated inflammatory immune response is triggered. This response cannot be shut off by the normal mechanisms of the immune system.1
This inflammatory state is associated with an abnormal activation of T cells and macrophages, resulting in excessive cytokine production and hyperinflammation.2
The threshold model of HLH
The threshold model of HLH is used to illustrate the potential for HLH to occur when a combination of factors causes a critical threshold to be reached. These factors can include genetic susceptibility and hyperinflammatory contributors such as infections, rheumatic disease, or malignancies.3,4
Research on the specific triggers of MAS in the context of underlying rheumatic disease is ongoing, but infections or other stressors, in combination with background inflammation or hypomorphic defects in cytolytic genes, have been shown to play a role.1,5,6
Consistent with the threshold model:
Infections and other stressors can combine with the chronic inflammation in patients with underlying rheumatic disease, reaching a critical threshold at which MAS develops.1
Genetic susceptibility may also play a role in some patients with partial loss-of-function mutations in genes that control cytotoxic function or immune system regulation.1
Interferon gamma (IFNγ) is a key player in the hyperinflammatory mechanism of MAS7,8
High IFNγ promotes a dangerous feedback loop of hyperinflammation
IFNγ is a key cytokine that activates macrophages. In patients with HLH, these macrophages produce an excess of proinflammatory cytokines through a dysregulated feedback loop.7,8
In systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD), IL-18 and other proinflammatory cytokines are elevated as a characteristic of underlying rheumatic disease. IL-18 promotes IFNγ production in NK cells, T cells, and macrophages.2,5,8
Hypomorphic genetic defects, chronic inflammation, or infectious triggers may overlap to trigger a dysregulated inflammatory state.1,5,9
High IFNγ levels over activate macrophages and increase monocyte sensitivity to IFNγ stimulation.10
Activated macrophages release proinflammatory cytokines including IL-1β, IL-6, IL-18, and TNF-α, which are responsible for the cytokine storm in MAS.8
A continuous feedback loop of cytokine production and macrophage activation results in hyperinflammation and irreversible multiorgan damage.2
In systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD), IL-18 and other proinflammatory cytokines are elevated as a characteristic of underlying rheumatic disease. IL-18 promotes IFNγ production in NK cells, T cells, and macrophages.2,5,8
Hypomorphic genetic defects, chronic inflammation, or infectious triggers may overlap to trigger a dysregulated inflammatory state.1,5,9
High IFNγ levels over activate macrophages and increase monocyte sensitivity to IFNγ stimulation.10
Activated macrophages release proinflammatory cytokines including IL-1β, IL-6, IL-18, and TNF-α, which are responsible for the cytokine storm in MAS.8
A continuous feedback loop of cytokine production and macrophage activation results in hyperinflammation and irreversible multiorgan damage.2
References: 1. Lerkvaleekul B, Vilaiyuk S. Macrophage activation syndrome: early diagnosis is key. Open Access Rheumatol. 2018;10:117-128. doi:10.2147/OARRR.S151013 2. 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 3. Henter JI. Hemophagocytic lymphohistiocytosis. N Engl J Med. 2025;392(6):584-598. doi:10.1056/NEJMra2314005 4. 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 5. 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 6. Monteagudo LA, Boothby A, Gertner E. Continuous intravenous anakinra infusion to calm the cytokine storm in macrophage activation syndrome. ACR Open Rheumatol. 2020;2(5):276-282. doi:10.1002/acr2.11135 7. De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. Targeting interferon-γ in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol. 2021;17(11):678-691. doi:10.1038/s41584-021-00694-z 8. 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 9. Henderson LA, Cron RQ. Macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis in childhood inflammatory disorders: diagnosis and management. Paediatr Drugs. 2020;22(1):29-44. doi:10.1007/s40272-019-00367-1 10. Pascarella A, Bracaglia C, Caiello I, et al. Monocytes from patients with macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis are hyperresponsive to interferon gamma. Front Immunol. 2021;12:663329. doi:10.3389/fimmu.2021.663329 11. Rocco JM, Oved JH, Patel RJ, et al. CXCL9 as a novel prognostic marker to identify high-risk adults with hemophagocytic lymphohistiocytosis. Blood. 2026;147(9):960-972. doi:10.1182/blood.2025030976
