Interferon-Gamma (IFNg) in Macrophage Activation Syndrome (MAS): CXCL9 Levels As a Biomarker for IFNg Production in MAS

Claudia Bracaglia¹, Denise Pires Marafon², Ivan Caiello¹, Kathy De Graaf³, Florence Guilhot⁴, Walter Ferlin⁴, Sergio Davì⁵, Grant Schulert⁶, Angelo Ravelli⁵, Alexei A. Grom⁷, Robert Nelson⁴, Cristina de Min⁴ and Fabrizio De Benedetti¹, ¹Department of Pediatric Medicine, Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy, ²Pediatric Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy, ³Novimmune S.A., Geneva, Switzerland, ⁴NovImmune S.A., Geneva, Switzerland, ⁵Istituto Giannina Gaslini and University of Genova, Genova, Italy, ⁶Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ⁷Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

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

Session Information

Date: Tuesday, November 10, 2015

Title: Pediatric Rheumatology - Clinical and Therapeutic Aspects III: Miscellaneous Pediatric Rheumatic Diseases

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: A vast body of evidence in animals and humans points to
a pivotal pathogenic role of IFNγ, in primary HLH.
The role of IFNg in HLH secondary
to rheumatic diseases, usually referred to as MAS, remains to be established. We have previously reported high
levels of IFNg and of the three IFNγ-related chemokines, CXCL9, CXCL10 and CXCL11 in
patients with active MAS, in the context of systemic Juvenile Idiopathic
Arthritis (sJIA) (1). Indirect evidence in mice suggests that IFNγ is mostly produced in
peripheral tissues and blood concentrations may be relatively low.

Methods : Circulating levels of IFNγ, CXCL9, CXCL10,
CXCL1, IL-1b and IL-6 in patients with sJIA
(n=54) of whom 20 had MAS at time of sampling were measured by Luminex multiplexing assay. We evaluated the correlation between serum levels of IFNg and of the three IFNg related chemokines with themselves and with
laboratory parameters of disease activity in active MAS.

Results: Levels of IFNγ and of the 3 IFNγ-related chemokines were significantly elevated in
active MAS compared to active sJIA without MAS at
sampling (all p-values <0.005). In patients with active MAS, but not in
patients with active sJIA without MAS at sampling,
laboratory parameters of disease severity (ferritin, neutrophils, platelets,
alanine aminotransferase and lactate dehydrogenase) were significantly
correlated with IFNγ and CXCL9, and to a lesser
extent with CXCL10 and CXCL11 (Table1). No correlation with IL-6 levels was
found. In active MAS IFNg levels were significantly
correlated with levels of CXCL9 (r=0.69; r²=0.48; p=0.001), but not
with those of CXCL10 (r=0.54; r²=0.29; p=0.015), or CXCL11 (r=-0.04;
r²=0.0016; p=0.887).

Conclusion: High levels of IFNγ and
of CXCL9 during active MAS were significantly correlated with laboratory parameters
of disease severity. Since CXCL9 has been shown to be induced only by IFNg and not by other interferons (2), our findings
support the conclusion that CXCL9 is a potential biomarker of IFNg production in MAS.

References.

1. Bracaglia C., Caiello I, De Graaf
K., et al. Pediatric Rheumatology 2014, 12(Suppl
1):O3.

2. Groom J.R. and Luster
A.D. Immunol Cell Biol
2011, Feb; 89(2): 207-15.

Table1. Correlation of laboratory
parameters of disease activity with IFNg, CXCL9, CXCL10, CXCL11 and IL-6 in patients with MAS
and in patients with active sJIA.

	Macrophage Activation Syndrome	IFNg		CXCL9		CXCL10		CXCL11		IL-6
	Macrophage Activation Syndrome	r*	p	r*	p	r*	p	r*	p	r*	p
Ferritin	8000 (3158.5 – 13174)	0.57	0.014	0.49	0.041	0.66	0.002	0.62	0.023	0.17	>0.1
N	6.9 (3.4 – 13.9)	-0.64	0.005	-0.61	0.010	-0.37	>0.1	-0.08	>0.1	0.09	>0.1
PLT	198 (115 – 392)	-0.53	0.017	-0.52	0.022	-0.58	0.008	-0.22	>0.1	-0.02	>0.1
ALT	46 (18 – 164)	0.49	0.045	0.49	0.044	0.51	0.038	0.06	>0.1	-0.44	0.080
LDH	1152 (722 – 2135)	0.45	0.095	0.62	0.013	0.64	0.010	0.64	0.048	0.08	>0.1
	Systemic Juvenile Arthritis	IFNg		CXCL9		CXCL10		CXCL11		IL-6
	Systemic Juvenile Arthritis	r*	p	r*	p	r*	p	r*	p	r*	p
Ferritin	215 (38 – 1669)	-0.27	>0.1	0.28	>0.1	0.27	>0.1	0.29	>0.1	-0,12	>0.1
N	8.4 (5.2 – 14.5)	0.30	>0.1	0.40	0.061	0.32	>0.1	0.40	0.067	0,28	>0.1
PLT	444 (353 – 544)	0.21	>0.1	-0.14	>0.1	-0.13	>0.1	0.27	>0.1	0,35	0.064
ALT	16 (11 – 24)	0.29	>0.1	0.42	0.049	0.50	0.011	0.44	0.039	0,04	>0.1
LDH	506 (456 – 851)	0.07	>0.1	0.49	>0.1	0	>0.1	0.26	>0.1	0	>0.1
N=neutrophils count; PLT= platelets count; ALT= alanine aminotransferase; ¹=Median (IQR); r*= Spearman r

Disclosure: C. Bracaglia, None; D. Pires Marafon, None; I. Caiello, None; K. De Graaf, Novimmune, 3; F. Guilhot, NovImmune SA, 3; W. Ferlin, Novimmune, 3; S. Davì, None; G. Schulert, None; A. Ravelli, None; A. A. Grom, Novartis, Roche, 5; R. Nelson, NovImmune SA, 3; C. de Min, Novimmune, 3; F. De Benedetti, None.

To cite this abstract in AMA style:

Bracaglia C, Pires Marafon D, Caiello I, De Graaf K, Guilhot F, Ferlin W, Davì S, Schulert G, Ravelli A, Grom AA, Nelson R, de Min C, De Benedetti F. Interferon-Gamma (IFNg) in Macrophage Activation Syndrome (MAS): CXCL9 Levels As a Biomarker for IFNg Production in MAS [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/interferon-gamma-ifng-in-macrophage-activation-syndrome-mas-cxcl9-levels-as-a-biomarker-for-ifng-production-in-mas/. Accessed .

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-gamma-ifng-in-macrophage-activation-syndrome-mas-cxcl9-levels-as-a-biomarker-for-ifng-production-in-mas/