IL-38 as a Marker of Immunoregulatory Reserve in Gout
Keywords:
gout, hyperuricemia, IL-38, systemic inflammation, SII, NLR, SIRI, ROC analysis, CRP, logistic regressionAbstract
Gout is a metabolic-inflammatory disease in which hyperuricemia fuels crystal-induced inflammation, and clinical variability is often determined not only by uric acid levels but also by the balance between systemic inflammation and anti-inflammatory regulation. Interleukin-38 (IL-38), potentially reflecting the "inhibitory reserve" of the inflammatory response, is considered a promising marker of the immunoregulatory system.
To assess IL-38 levels in patients with gout and determine its relationship with clinical disease activity and systemic immune-inflammatory indices, as well as to establish an IL-38 threshold for stratifying the risk of an unfavorable course.
A single-center comparative study was conducted including two groups: patients with gout (n=120) and a comparison group without gout and hyperuricemia (n=90). Clinical and anamnestic assessment (frequency of attacks over 12 months, pain intensity according to VAS, presence of tophi), biochemical examination (SUA, creatinine, eGFR calculation), inflammatory markers (CRP, ESR) and complete blood count with calculation of NLR, SII and SIRI were performed. IL-38 levels were determined by ELISA. Statistical analysis included the U-test/t-test, Spearman correlations, multivariate logistic regression (unfavorable course: ≥2 attacks/year) and ROC analysis to determine IL-38 cut-off.
IL-38 levels were lower in patients with gout compared to the comparison group: 47 [36; 62] versus 74 [58; 93] pg/ml (p<0.001). IL-38 was inversely associated with attack frequency (r=−0.34; p<0.001), pain VAS (r=−0.29; p=0.002), CRP (r=−0.31; p=0.001) and SII (r=−0.37; p<0.001). Patients with frequent attacks (≥2/year) were characterized by lower IL-38: 39 [30; 52] versus 55 [41; 69] pg/ml (p<0.001) and higher SII (p<0.001). In a multivariate model, IL-38 maintained an independent protective association with an unfavorable course (OR=0.83 per +10 pg/mL; 95% CI 0.72–0.95; p=0.008) after accounting for age, gender, SUA, and CRP. ROC analysis showed a moderately good predictive ability of IL-38 for ≥2 attacks/year: AUC=0.73 (95% CI 0.64–0.81); the optimal threshold of ≤45 pg/mL provided a sensitivity of 68% and specificity of 67%.
Low IL-38 in patients with gout is associated with higher clinical activity and increased systemic inflammation according to integrated blood indices. IL-38 demonstrates an independent protective association with the risk of frequent attacks and can be considered as a candidate marker for early risk stratification and personalized monitoring.
References
1. Dalbeth N, Gosling AL, Gaffo A, Abhishek A. Gout. Lancet. 2021;397(10287):1843–1855. doi:10.1016/S0140-6736(21)00569-9.
2. Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016;388(10055):2039–2052. doi:10.1016/S0140-6736(16)00346-9.
3. Dehlin M, Jacobsson L, Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020;16(7):380–390. doi:10.1038/s41584-020-0441-1.
4. Chen-Xu M, Yokose C, Rai SK, Pillinger MH, Choi HK. Contemporary prevalence of gout and hyperuricemia in the United States and decadal trends: NHANES 2007–2016. Arthritis Rheumatol. 2019;71(6):991–999.
5. Vos T, Lim SS, Abbafati C, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204–1222. doi:10.1016/S0140-6736(20)30925-9.
6. FitzGerald JD, Dalbeth N, Mikuls TR, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Rheumatol. 2020;72(6):879–895. doi:10.1002/art.41247.
7. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29–42. doi:10.1136/annrheumdis-2016-209707.
8. Rock KL, Kataoka H, Lai JJ. Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol. 2013;9(1):13–23. doi:10.1038/nrrheum.2012.143.
9. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–241. doi:10.1038/nature04516.
10. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9(2):R28. doi:10.1186/ar2143.
11. Dalbeth N, Choi HK, Joosten LAB, et al. Gout. Nat Rev Dis Primers. 2019;5(1):69. doi:10.1038/s41572-019-0115-y.
12. Esmaeilzadeh A, Elahi R, Abdi K, et al. Interleukin-38: immunobiological properties and clinical applications. Cell Mol Life Sci. 2021;78(19):6565–6583. doi:10.1007/s00018-021-03872-8.
13. Li H, Liu T, Chen S, et al. Decreased serum interleukin-38 in gout with its relation to inflammation and renal function. Acta Med Mediterr. 2024;40(2):729–736. doi:10.19193/0393-6384_2024_2_106.
14. Kanbay M, Jensen T, Solak Y, et al. Uric acid in metabolic syndrome: from an innocent bystander to a central player. Eur J Intern Med. 2016;29:3–8.
15. Safiri S, Kolahi A-A, Cross M, et al. Global, regional, and national burden of gout, 1990–2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann Rheum Dis. 2020;79(1):31–38.
16. Panahi Y, Hosseini MS, Khalili N, et al. Effects of curcumin on serum cytokines and inflammatory markers: a systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2016;30(10):1524–1533.
17. Akbari M, Tamtaji OR, Lankarani KB, et al. The effects of curcumin on glycemic control and insulin resistance: a systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2019;33(1):3–14.
18. Dehlin M, Jacobsson L, Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020;16(7):380–390. doi:10.1038/s41584-020-0441-1.
