From the Guidelines
High IL-18 levels are clinically significant as they indicate active inflammation and immune system activation, and should be evaluated in the context of underlying autoimmune disorders, infections, or other inflammatory conditions, as suggested by the 2024 EULAR/PReS recommendations for the diagnosis and management of Still's disease 1. Elevated interleukin-18 is associated with several inflammatory conditions including rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and certain infectious diseases. IL-18 functions as a pro-inflammatory cytokine that stimulates interferon-gamma production and enhances natural killer cell activity. When levels are elevated, this suggests ongoing inflammatory processes that may require medical intervention. Some key points to consider in the evaluation of high IL-18 levels include:
- The degree of elevation often correlates with disease severity, making it a useful biomarker for clinical assessment and treatment decisions in inflammatory conditions 1.
- Marked elevation of serum IL-18 and/or S100 proteins strongly supports the diagnosis of Still's disease, and therefore should be measured if available 1.
- Alternative diagnoses such as malignancies, infectious diseases, other immune-mediated inflammatory diseases, and monogenic autoinflammatory disorders should be carefully considered 1.
- Treatment typically targets the underlying cause rather than IL-18 directly, often involving anti-inflammatory medications, immunosuppressants, or biologics depending on the specific diagnosis.
- Monitoring IL-18 levels over time can help assess treatment effectiveness and disease progression. It is essential to consider the clinical context and other diagnostic criteria when evaluating high IL-18 levels, as they can be associated with various conditions, including Still's disease, macrophage activation syndrome (MAS), and other inflammatory disorders 1.
From the Research
Significance of High IL-18 Levels
- High IL-18 levels are associated with various immune-mediated inflammatory diseases, including systemic juvenile idiopathic arthritis and adult-onset Still's disease 2.
- Elevated serum IL-18 levels are linked to a high incidence of macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) in certain diseases, such as X-linked inhibitor of apoptosis deficiency and NLRC4-associated autoinflammatory disease 2, 3.
- IL-18 plays a crucial role in the pathogenesis of hemophagocytic syndromes, and its levels can be used as a biomarker for diagnosis and treatment monitoring 3, 4.
- High IL-18 levels are also associated with an increased risk of developing cardiovascular disease and a worse prognosis in patients with established cardiovascular disease 5.
- In sepsis, elevated plasma IL-18 concentrations are associated with poor clinical outcome, and IL-18 may serve as a prognostic cytokine in bacteria-induced sepsis 6.
Clinical Relevance
- Understanding the pathology of diseases associated with high IL-18 levels is crucial for the development of effective therapeutic strategies 2.
- IL-18 binding protein (IL-18BP) and neutralizing IL-18 antibodies have been investigated as potential therapeutic approaches for diseases characterized by high IL-18 levels, including rheumatoid arthritis, psoriasis, and heart disease 3, 5.
- Targeted treatment of inflammatory and malignant diseases using IL-18 agonist treatments shows promise, particularly in augmenting immune responses to cancer 4.
Biological Properties
- IL-18 is a proinflammatory cytokine that promotes various innate immune processes related to infection, inflammation, and autoimmunity 2, 3.
- IL-18 binds to its specific receptor, forming a low-affinity ligand chain, and uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators 3.
- IL-18 also binds to the circulating high-affinity IL-18 binding protein (BP), which acts as a sink for the anti-inflammatory properties of IL-37 3.