Inflammatory Biomarkers in MAS

Elevated biomarkers of inflammation associated with MAS

Certain biomarkers of inflammation can measure key disease pathways. These often become elevated during macrophage activation syndrome (MAS) episodes, and their specificity may be helpful in identifying MAS.¹ See below for a table containing key biomarkers to assess in patients with suspected MAS, and their relation to the underlying pathology.

	Inflammatory biomarkers	Biology
STANDARD LAB ASSESSMENTS¹
STANDARD LAB ASSESSMENTS¹	CRP	Hepatic release in response to systemic inflammation (IL-6)
	ESR	Initially elevated due to systemic inflammation but may later decline due to fibrinogen consumption
	Ferritin	Macrophage/hepatocyte activation
	LDH	General marker of cellular death
SPECIALIZED LAB ASSESSMENTS^1-3
SPECIALIZED LAB ASSESSMENTS^1-3	CD163	Macrophage activation
	CXCL9	Chemokine induced by IFNγ; marker for IFNγ activity
	IL-18	Inflammasome activated; induces IFNγ
	Neopterin (macrophage)	Metabolite of GTP, induced by IFNγ
	sCD25	Marker of T-cell activation

CD=cluster of differentiation; CRP=C-reactive protein; CXCL9=(C-X-C motif) ligand 9; ESR=erythrocyte sedimentation rate; GTP=guanosine triphosphate; IFNγ=interferon gamma; IL=interleukin; LDH=lactate dehydrogenase; sCD25=soluble cluster of differentiation 25.

CXCL9 is a recognized marker for IFNγ activity⁴

IFNγ is a key driver of the hyperinflammatory response in MAS in Still's disease and selectively induces CXCL9.⁴

CXCL9 is⁵:

Stable and easily measurable in serum
Reflective of IFNγ production and activation of IFNγ-induced signaling pathways
Useful as both an ancillary diagnostic tool and an emerging marker of treatment response

Monitoring CXCL9 levels may be helpful in distinguishing MAS from a flare of the background rheumatic condition⁴

Evaluating
CXCL9 levels

In a cross-sectional analysis of blood samples from patients with sJIA, including those with active MAS, active sJIA without MAS, and healthy controls, researchers measured levels of IFNγ and IFNγ-induced CXCL9. Their findings suggest that IFNγ is a key driver of the hyperinflammation seen in MAS, but not the persistent autoinflammation of underlying sJIA.⁴

Serum levels of IFNγ and CXCL9 are elevated in MAS in sJIA⁴

	MAS (n=20)	Active sJIA (n=28)
IFNγ pg/mL (range)	15.4 (5.1-52.6)	4.9 (3.2-8.6)
CXCL9 pg/mL (range)	13,392 (2163-35,452)	837 (471-2505)

CXCL9 levels have been shown to correlate with several laboratory features of MAS in sJIA and decrease with reductions in disease activity.⁵

CXCL9 testing sites

There is growing recognition of testing for CXCL9 as a biomarker for IFNγ activity.^5,6 The following organizations offer CXCL9 testing  to help with identifying MAS:

Machaon Diagnostics
Website	machaondiagnostics.com/test/cxcl9-level
Turnaround time	STAT: <24 hours Routine: <1 week
Lab hours	24/7
Phone	1-800-566-3462 510-839-5600
Fax	510-839-6153

Cincinnati Children’s Hospital
Website	testmenu.com/cincinnatichildrens/Tests/723501
Turnaround time	4 days
Lab hours	Mon-Fri, 8:00 AM to 5:00 PM (ET)
Phone	513-636-4685
Fax	513-636-3861

This is not an exhaustive list of labs offering CXCL9 testing. Please check for the availability of this test within your own institution prior to contacting these sites.

MAS overview

Learn more about the signs and manifestations of MAS.

Learn more about MAS

References

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). Ann Rheum Dis. 2023;82(10):1271-1285. doi:10.1136/ard-2023-224123
Sen ES, Clarke SLN, Ramanan AV. Macrophage activation syndrome. Indian J Pediatr. 2016;83(3):248-253. doi:10.1007/s12098-015-1877-1
Di Cola I, Ruscitti P, Giacomelli R, Cipriani P. The pathogenic role of interferons in the hyperinflammatory response on adult-onset Still’s disease and macrophage activation syndrome: paving the way towards new therapeutic targets. J Clin Med. 2021;10(6):1164. doi:10.3390/jcm10061164
Bracaglia C, de Graaf K, Pires Marafon D, et al. Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(1):166-172. doi:10.1136/annrheumdis-2015-209020
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
Cincinnati Children’s. From the Clinical Laboratories of the Cancer & Blood Diseases Institute. CXCL9. 2019.

Elevated biomarkers of inflammation associated with MAS

CXCL9 is a recognized marker for IFNγ activity⁴

Monitoring CXCL9 levels may be helpful in distinguishing MAS from a flare of the background rheumatic condition⁴

CXCL9 testing sites

MAS overview

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

Elevated biomarkers of inflammation associated with MAS

CXCL9 is a recognized marker for IFNγ activity4

Monitoring CXCL9 levels may be helpful in distinguishing MAS from a flare of the background rheumatic condition4

CXCL9 testing sites

MAS overview

INDICATIONS

IMPORTANT SAFETY INFORMATION

Infections

Increased Risk of Infection With Use of Live Vaccines

Infusion-Related Reactions

Adverse Reactions

Primary HLH

HLH/MAS

References

CXCL9 is a recognized marker for IFNγ activity⁴

Monitoring CXCL9 levels may be helpful in distinguishing MAS from a flare of the background rheumatic condition⁴