Estudio de la interleucina-18 y otras citoquinas en el líquido sinovial de pacientes con artritis idiopática juvenil

Abstract

BACKGROUND: The inflammasome is a cytoplasmic multiprotein complex that induces an inflammatory reaction after releasing cytokines such as interleukin (IL)-1β and IL-18. IL-18 can be blocked by a high affinity protein called IL-18 binding protein. The IL-18/IL-18BP imbalance with an increase in free IL-18 has been associated with immune-mediated diseases and is correlated with severity and activity, proposing it as a possible therapeutic target. OBJECTIVES: To study the involvement of inflammasome products and other cytokines in juvenile idiopathic arthritis by detecting them in synovial fluid. MATERIAL AND METHODS: Synovial fluid samples were collected from January 2019-January 2021 from a cohort of patients diagnosed with Juvenile Idiopathic Arthritis, joint infection and osteoarthritis at the Virgen de la Arrixaca University Clinical Hospital (HCUVA) in Murcia, after signing the consent form. informed and approval of the Ethics Committee. Clinical variables such as age, sex, autoimmune markers, affected joint, debut or outbreak, cytobiochemistry and microbiology of the synovial fluid, personal and family history, and treatment were studied; and a total of 16 cytokines/chemokines were analyzed in the synovial fluid (IL-18, IL-18BP, INFγ, IL-1α, IL-1β, IL-10, IL-12p70, IL-17A, IL-1RA, IL -2, IL-4, IL-6, RANKL, TNFα, MIP-1α and MIP-1β). The IL-18 binding protein (IL-18BP) was studied by enzyme-linked immunosorbent assay (ELISA), and the rest by multiplex multiplex assay. The ratio between the concentration of IL-18 and IL-18BP was also calculated for each patient. Statistical analysis was performed. RESULTS: A total of 61 synovial fluid samples were collected, corresponding to 46 JIA patients (1 systemic JIA, 34 oligoarticular JIA, 1 positive RF polyarticular JIA, 6 negative RF polyarticular JIA, 2 psoriatic JIA, and 2 enthesitis-associated arthritis ) and were compared with 11 patients with osteoarthritis and 4 patients with infectious arthritis. In the JIA group, 84.78% of the samples were collected in the bud, especially in the knee (91.3%). The cytobiochemistry of the fluid showed a mean leukocyte count of 9653 cells/μL (62.81% mononuclear), with a negative culture. 43.48% had a personal history of other autoimmune diseases and 28.26% had a family history. Half received treatment prior to collection, especially a combination of classic DMARDs and biological DMARDs. The significant increase in IL-18 and IL-18BP in JIA versus osteoarthritis was not observed when calculating the ratio. However, a significant increase in the IL-18/IL-18BP ratio was obtained in oligoarticular JIA versus polyarticular JIA (p=0.002). The rest of the cytokines presented higher concentrations in the JIA group compared to the rest, but they were not significant. In JIA, IL-18 (p=0.04), IL-10 (p= 0.01), IL-1RA (p= 0.04), and MIP-1β (p= 0.001) were significantly elevated in debut patients versus outbreak. However, IL-12p70 (p= 0.02), IL-2 (p= 0.01) and RANKL (p= 0.04) were significantly higher in flare. The IL-18/IL-18BP ratio was significantly elevated in patients without treatment at the time of collection (p=0.002). CONCLUSION: Our study analyzes for the first time the concentration of IL-18, IL-18BP and the ratio of both in synovial fluid. The IL-18/IL-18BP ratio was significantly elevated in oligoarticular JIA versus polyarticular JIA and in patients without treatment prior to collection, which may mean a higher concentration of free IL-18 in these cases. Measurement of the IL-18/IL-18BP ratio or free IL-18 in synovial fluid could be used as a marker of severity and a differentiator between arthropathies and therapies aimed at blocking IL-18 could be useful to treat JIA patients.