From the Guidelines
An IL-18 level 100 times higher than normal indicates a significant inflammatory response that requires immediate medical attention, and treatment should involve high-dose corticosteroids and consideration of additional immunosuppression with IL-1 or IFN-γ inhibitors, as recommended by the EULAR/PReS guidelines 1. This extreme elevation is commonly associated with macrophage activation syndrome (MAS), hemophagocytic lymphohistiocytosis (HLH), or severe autoinflammatory conditions like adult-onset Still's disease.
- Key features of these conditions include:
- Fever, rash, and musculoskeletal involvement
- High levels of inflammation, as indicated by neutrophilic leucocytosis, increased serum CRP, and ferritin
- Marked elevation of serum IL-18 and/or S100 proteins, which strongly supports the diagnosis of Still's disease 1
- The EULAR/PReS guidelines recommend early initiation of IL-1 or IL-6 inhibitors, which have been shown to lead to high levels of rapid GC-free clinical inactive disease (CID) in patients with Still's disease 1.
- For patients with MAS, high-dose GCs are the mainstay of treatment, and novel therapies targeting IL-1 or IFN-γ may be effective in patients who fail high-dose GCs 1.
- Supportive care, including hospitalization for close monitoring of organ function, complete blood counts, and inflammatory markers, is essential in managing these conditions.
- IL-18 is a pro-inflammatory cytokine produced by macrophages that activates natural killer cells and T cells, promoting interferon-gamma production, and such dramatically elevated levels suggest a dangerous cytokine storm that can lead to multi-organ failure if not promptly addressed 1.
From the Research
Elevated IL-18 Levels
- IL-18 levels 100 times higher than normal may be associated with various inflammatory and infectious diseases, including hemophagocytic syndromes, systemic juvenile idiopathic arthritis, and adult-onset Still's disease 2.
- Elevated IL-18 concentrations have been linked to poor clinical outcomes in severe inflammatory and septic conditions, and may be used as a prognostic cytokine in bacteria-induced sepsis 3.
Role of IL-18 in Disease Pathogenesis
- IL-18 plays a crucial role in the activation of Th1 and NK cells, and the production of inflammatory mediators such as adhesion molecules, chemokines, and Fas ligand 2, 4.
- IL-18 has been implicated in the pathogenesis of various diseases, including influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, and Crohn's disease 2.
- IL-18 dysregulation can be a primary driving feature of certain autoinflammatory diseases, known as "IL-18opathies" 5.
Therapeutic Perspectives
- Targeting IL-18 may present a novel approach for the treatment of diabetes mellitus and its complications, as well as other inflammatory diseases 6.
- IL-18 inhibitors, including chemical and natural inhibitors, have been developed and may be used to protect against diabetes and diabetic complications 6.
- Biological neutralization of IL-18 via caspase-1 intervention or through the administration of IL-18-binding protein has been proposed as a promising therapeutic approach for acute inflammatory diseases 3.