Biomarkers for the Diagnosis and the Identification of Risk of Macrophage Activation Syndrome (MAS) in Systemic Juvenile Idiopathic Arthritis (sJIA)

Claudia Bracaglia¹, Denise Pires Marafon², Ivan Caiello³, Kathy de Graaf⁴, Maria Ballabio⁴, Walter Ferlin⁴, Sergio Davì⁵, Grant Schulert⁶, Angelo Ravelli⁷, Alexei A. Grom⁸, Robert Nelson⁴, Cristina de Min⁴ and Fabrizio De Benedetti², ¹Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy, ²Division of Rheumatology, IRCCS Bambino Gesù Children's Hospital, Rome, Rome, Italy, ³Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy, Rome, Italy, ⁴NovImmune S.A., Geneva, Switzerland, ⁵University of Genova, IRCCS Istituto Giannina Gaslini, Genoa, Italy, ⁶Pediatric Rheumatology, Division of Pediatric Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, ⁷University of Genova, IRCCS Istituto Giannina Gaslini, Genova, Italy, ⁸Division of Pediatric Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States Minor Outlying Islands

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: cytokines, interferons and macrophage activation syndrome, Systemic JIA

Session Information

Date: Tuesday, November 7, 2017

Title: Pediatric Rheumatology – Pathogenesis and Genetics Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: We have recently reported high levels of IFNγ and of the IFNγ-related chemokines, (CXCL9 and CXCL10) in patients with MAS (1).

Methods: Circulating levels of IFNγ, CXCL9, CXCL10, IL-18, neopterin and sCD25 IFNγ, CXCL9, CXCL10, IL-18, neopterin and sCD25 were measured by Luminex assay in 57 samples obtained from 24 patients with active sJIA and in 37 samples from 20 MAS patients with variable degrees of disease severity and under different treatments at time of sampling. We evaluated if blood levels of these biomarkers may help to identify sJIA patients with the predisposition to develop MAS, and additionally if they may help clinicians to distinguish MAS from active sJIA.

Results: Levels of IFNγ, CXCL9, CXCL10, IL-18, neopterin and sCD25 were significantly elevated in MAS compared to active sJIA without MAS at sampling (p-values <0.0001, except for IL-18 p=0.012) and were significantly correlated with laboratory parameters of disease severity, except for IL-18, whose levels were available only for a portion of the samples. During active sJIA without MAS at sampling, levels of the IFNγ-induced chemokines (CXCL9 and CXCL10) were significantly higher in patients with a history of MAS as compared to those of patients without a history of MAS (Table 1). In order to verify if measurement of these biomarkers could help in distinguishing MAS from active sJIA, we analyzed sensitivity and specificity and the area under the curve (AUC) for each parameter. The highest AUC (=0.95) was found for neopterin levels >14.62 nmol/L (Sensitivity 85.3% Specificity 84.6%). AUC for IFNγ (>8.5 pg/ml), CXCL9 (>2677 pg/ml), CXCL10 (>725.5 pg/ml), IL-18 >(4309 pg/ml) and sCD25 (>211.65 pg/ml) were 0.77, 0.82, 0.82, 0.82 and 0.86, respectively.

Table 1. Cytokine levels in sJIA patients with active disease with or without history of MAS

	sJIA with history of MAS (N=17)	sJIA without history of MAS (N=40)	P
IFNγ (pg/ml)	5.6 (3.2-14.4)	5.3 (3.2-10)	0.74
CXCL9 (pg/ml)	3889 (965-7142)	519 (385-1168)	0.0015
CXCL10 (pg/ml)	764 (323-1259)	215 (152-470)	0.0003
IL-18 (pg/ml)	4405 (582-7122)	439 (312-824)	0.067
neopterin (nmol/L)	8.2 (6.5-13.9)	8.1 (6.6-8.8)	0.94
sCD25 (pg/ml)	80 (80-229)	80 (80-193)	1
Values are expressed as median (IQR)

Conclusion: Elevation of neopterin and CXCL9, both reflecting IFNγ production, and their correlation with laboratory parameters, supports the pathogenic role of IFNγ in MAS. Circulating levels of CXCL9 and CXCL10 (to a lesser extent of IL-18, though, not reaching statistical significance) are higher in patients with a history of MAS compared to patients without a history of MAS, suggesting subclinical activation of this pathway even in the absence of overt MAS and that CXCL9 and CXCL10 may identify patients at high risk for MAS; larger studies are needed. Regarding distinguishing MAS from active sJIA, levels of neopterin, IFNγ, CXCL9, CXCL10, sCD25, and IL-18 may be used and the possibility to integrate the currently available classification criteria with one or more of these biomarkers investigated in larger studies.

Reference. 1. Bracaglia C, et al. Ann Rheum Dis. 2017 Jan; 76(1):166-172.

Disclosure: C. Bracaglia, None; D. Pires Marafon, None; I. Caiello, None; K. de Graaf, Novimmune, 3; M. Ballabio, Novimmune, 3; W. Ferlin, Novimmune, 3; S. Davì, None; G. Schulert, None; A. Ravelli, None; A. A. Grom, NovImmune, Novartis Pharmaceutical Corporation, Roche Pharmaceuticals, 2; R. Nelson, NovImmune, 3; C. de Min, NovImmune, 3; F. De Benedetti, Novartis, Roche, Pfizer, SOBI, AbbVie, Novimmune, BMS, Sanofi, 2.

To cite this abstract in AMA style:

Bracaglia C, Pires Marafon D, Caiello I, de Graaf K, Ballabio M, Ferlin W, Davì S, Schulert G, Ravelli A, Grom AA, Nelson R, de Min C, De Benedetti F. Biomarkers for the Diagnosis and the Identification of Risk of Macrophage Activation Syndrome (MAS) in Systemic Juvenile Idiopathic Arthritis (sJIA) [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/biomarkers-for-the-diagnosis-and-the-identification-of-risk-of-macrophage-activation-syndrome-mas-in-systemic-juvenile-idiopathic-arthritis-sjia/. Accessed .

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