Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Macrophage Activation Syndrome (MAS) is a life-threatening systemic inflammatory syndrome that complicates several rheumatic diseases. Current MAS-related serum biomarkers (ferritin, neopterin, CD163, and CD25) mark active disease but normalize with quiescence and may lack specificity. Serum IL-18 elevation has been associated with many inflammatory and infectious diseases, but extremely high levels have been reported in Still’s Disease and Systemic Juvenile Idiopathic Arthritis, particularly in patients with a history of MAS.
Methods: We measured serum levels of several cytokines across a complex cohort of patients with idiopathic or genetically-defined autoinflammatory diseases (NCT00059748). Samples were obtained from healthy adults (24 patients) and children (4), and patients with cryopyrinopathies (Neonatal Onset Multisystem Inflammatory Disease/NOMID (18) and Muckle-Wells Syndrome (1)), NLRC4-MAS (2), Non-infectious Osteomyelitis (3), Deficiency of IL-1 Receptor Antagonist (3), CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (3), SAVI (STING-Associated Vasculopathy with onset in Infancy (2), XIAP-deficiency (2) and undifferentiated (11). Cytokines were measured by Bio-Plex Luminex technology, except IL-37 (adipogene) and IL-18BP (R&D systems).
Results: We examined 142 samples from 27 controls and 49 patients. Of these patients, 13 had a clinical history of one to 4 episodes of MAS (as determined by the investigators based on the criteria established by Ravelli et al., J. Pediatr. 2005). Serum levels for total active IL-18, IL-18 binding protein (BP), and IL37 in healthy controls were 29-308, 3648-7889, and 40-505 pg/mL, respectively. Median serum IL-18 was 8773 (Interquartile Range (IQR) 1560-13581) pg/mL in patients with a history of MAS, and 176 (IQR 88-432) pg/mL in those without (p<0.0001, Mann-Whitney-U-test). Serum IL-18 levels did not correlate with disease activity or treatment, but stratified patients into normal, elevated (~10x normal), or extremely elevated (~100x normal) groups, with 12 of 13 MAS patients in the highest group. Levels of IL-18BP and IL-37, anti-inflammatory cytokines known to inhibit the bioactivity of IL-18 did not correlate with total IL-18. Interestingly, a patient with clinical NOMID but no NLRP3 mutation developed recurrent MAS and was our only cryopyrinopathy patient with chronically highly elevated IL-18 levels.
Conclusion: Extraordinary serum IL-18 elevation, even during quiescence, is associated with a clinical history of MAS. The utility of this biomarker in predicting MAS risk needs to be tested prospectively in patients at risk for developing MAS.
To cite this abstract in AMA style:Canna S, Almeida de Jesus A, Huang Y, Gouni S, Shi G, Gery I, Goldbach-Mansky R. Association of Chronic, Extreme Elevation of Serum IL-18 with the Development of Macrophage Activation Syndrome in a Cohort of Autoinflammatory Disease Patients: A Potential Diagnostic Biomarker? [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/association-of-chronic-extreme-elevation-of-serum-il-18-with-the-development-of-macrophage-activation-syndrome-in-a-cohort-of-autoinflammatory-disease-patients-a-potential-diagnostic-biomarker/. Accessed January 19, 2020.
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