Inflammatory biomarkers in MAS
Inflammatory biomarkers may help identify MAS
Understanding which signs, symptoms, and biomarkers to recognize offers the best chance of optimizing patient outcomes.1
Some inflammatory biomarkers can be measured to evaluate key disease pathways that can lead to cytokine storm syndromes, and their specificity may be helpful for identifying MAS.
These include:
Biomarker | Context |
CXCL9 | High serum levels of CXCL9, a chemokine selectively induced by IFNγ, can be observed with MAS onset and severity. Elevated CXCL9 levels may be helpful for differentiating MAS from an underlying rheumatic disease flare.2 CXCL9 has also been found to be useful as a predictor of mortality risk in adults with HLH.3 |
CRP | CRP, ESR, and LDH are commonly available tests that may help assess the extent of hyperinflammation in patients with suspected MAS.4 Persistently high CRP levels and increasing D-dimers, in combination with a fall in ESR and platelet count may suggest early stages of MAS development in febrile patients with underlying rheumatic disease. LDH is a general marker of cellular death or injury that is commonly elevated in patients with MAS.1,4,5 |
sCD25/sIL-2Rα | sCD25, also known as sIL-2Rα, is an inflammatory marker of T-cell activation that can be helpful for MAS diagnosis and as an indicator of treatment response.1,5 |
IL-18 | IL-18 testing can help measure inflammasome activation, which can lead to the development of MAS in certain contexts. Elevated IL-18 can be observed in patients with Still’s disease, but significant elevations above a patient’s baseline may suggest development of MAS.6,7 |
Neopterin | Neopterin and CD163 testing can indicate the activation and inflammatory status of macrophages, which are essential for MAS pathology.5,6,8 |
CRP=C-reactive protein; ESR=erythrocyte sedimentation rate; LDH=lactate dehydrogenase; sIL-2Rα=soluble interleukin 2 receptor alpha.
Some patients may experience recurrent MAS episodes. However, there is limited information about biomarkers or clinical factors that can predict this in patients.9
Monitoring trending lab values over time can provide important insights for assessing patients with MAS.8
A retrospective study:
CXCL9 as a novel prognostic marker to identify high-risk adults with hemophagocytic lymphohistiocytosis3
A retrospective, multicenter chart review was conducted to broadly evaluate potential clinical biomarkers, including CXCL9, to determine which combination of markers provides the greatest prognostic utility in a large cohort of individuals undergoing clinical HLH evaluation.
CXCL9 emerged as the only optimal predictor of inpatient mortality among all markers assessed, with risk increasing as CXCL9 levels rose.
Study limitations3
Retrospective design may be impacted by unrecognized confounders. Restricted to patients ≥15 years, limiting generalizability to younger populations. Variability in HLH recognition timing across patients and centers may introduce selection bias. Sensitivity analyses were conducted to mitigate bias.
Inclusion criteria3
Hospitalized patients ≥15 years undergoing HLH evaluation with ≥1 clinically validated CXCL9 test from a Clinical Laboratory Improvement Amendments (CLIA)-certified lab were included. Patients were excluded if CXCL9 testing occurred after initiation of HLH-directed therapy.
Patient characteristics3
171 adult patients were included and categorized as HLH- or HLH+. HLH+ was defined as meeting ≥4/8 HLH-2004 criteria and/or an HScore ≥169. Of 126 HLH+ patients, 73 met ≥5/8 HLH-2004 criteria.*
Key findings for clinical practice3
The authors reported that CXCL9, a surrogate marker for IFNγ, served as a novel and consistent clinical laboratory marker in the identification and prognosis of adults presenting with HLH.*
Elevated CXCL9 levels were associated with early mortality in HLH+ patients
Strength of association and mortality risk
In patients with HLH, CXCL9 emerged as the only optimal prognostic marker of inpatient mortality across all evaluated labs, with elevated levels significantly associated with early mortality.3
Increasing risk
Higher baseline CXCL9 levels were associated with progressively higher mortality risk, further supporting the strength of its prognostic utility.3
Decreased levels in survivors
Among patients with serial measurements, significant decreases in CXCL9 levels were observed more frequently in 90-day survivors.3
*Patients in the HLH+ cohort met at least 4 out of 8 HLH-2004 criteria and/or had an HScore ≥169. A cutoff of 4 out of 8 HLH-2004 criteria was used to capture a broad population including early HLH presentations and/or similar IFNγ-driven hyperinflammatory syndromes of which HLH represents the most severe manifestation. This modified cutoff also helped control for bone marrow biopsies not being routinely performed and a recent study suggested similar sensitivity when compared to the original cutoff.
Serial monitoring of absolute CXCL9 levels and their trajectory may help physicians evaluate the risk of mortality in patients with HLH.3
CXCL9 testing sites
cincinnatichildrens/Tests/723501
cxcl9-level
This is not an exhaustive list of labs offering CXCL9 testing, as additional labs continue to build new capabilities. Please check for the availability of this test within your own institution prior to contacting these sites.
References: 1. 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 2. 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 3. 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 4. Minoia F, Davì S, Horne A, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014;66(11):3160-3169. doi:10.1002/art.38802 5. Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12(5):259-268. doi:10.1038/nrrheum.2015.179 6. 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 7. 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 8. Lerkvaleekul B, Vilaiyuk S. Macrophage activation syndrome: early diagnosis is key. Open Access Rheumatol. 2018;10:117-128. doi:10.2147/OARRR.S151013 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
