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.

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ACR Meeting Abstracts - 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/