What happens in MAS?
MAS and underlying rheumatic disease
In 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
How is MAS triggered in patients with rheumatic disease?
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.1,3,4
Infections and other stressors can trigger prolonged immune activation in patients with underlying rheumatic disease. When this immune response cannot be resolved, overactivated T cells and macrophages can promote uncontrolled proinflammatory cytokine production.1,2,4
Hypomorphic genetic defects are mutations that cause a partial loss of gene function. Genetic defects that knock out cytolytic function have been implicated as a key factor in primary HLH pathogenesis. In MAS, patients may have similar defects that are less severe and result in only partial dysfunction—but this still leaves them susceptible to uncontrolled hyperinflammatory episodes.5
IFNγ is a key player in the hyperinflammatory mechanism of MAS6,7
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.6,7
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. 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 4. 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 5. 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 6. 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 7. 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 8. 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
