Various Inflammatory Cytokines Related to Etiology of Inflammatory Arthritis

A new analysis assessed the potential causality between inflammatory cytokines and three common inflammatory arthritis conditions, including Ankylosing spondylitis (AS), rheumatoid arthritis (RA), and psoriatic arthritis (PsA).¹

The bidirectional two-sample Mendelian randomization analysis revealed significant associations among 41 studied inflammatory cytokines and the 3 inflammatory arthritis conditions. According to the analysis, M-CSF, TRAIL, and β-NGF were positively correlated with the risk of AS, while interleukin (IL)-10, IL-12p70, IL-13, and vascular endothelial growth factor (VEGF) were related to the etiology of PsA, and IL-1rα displayed a positive association with the risk of RA.

“The genetic susceptibility of inflammatory arthritis is related to the levels of various inflammatory cytokines,” wrote the investigative team led by Cong Liu, department of spine and osteopathy ward, The First Affiliated Hospital of Guangxi Medical University. “This may provide new clues for the etiology, diagnosis, and treatment of inflammatory arthritis.”

Specific etiology and pathophysiology related to these inflammatory arthritis conditions are not well understood, but inflammation is believed to play a significant role in the development of immune-mediated diseases.² In particular, inflammatory cytokines may participate in the pathogenesis of inflammatory arthritis, leading to anti-inflammatory cytokine therapy becoming a critical treatment strategy for the conditions.

Several observational studies have attempted to understand the relationship between inflammatory cytokines and these diseases but determining the exact causal relationship can prove challenging due to confounding variables or reverse causality.³ Using summary data from a genome-wide association study (GWAS) with ≥8,000 individuals of European ancestry, Liu and colleagues performed a bidirectional two-sample MR analysis to assess the causal relationships between 41 inflammatory cytokines and AS, RA, and PsA.¹

GWAS summary statistics for AS, PsA, and RA were collected from the FinnGen consortium, a nationwide GWAS meta-analysis conducted across 9 biobanks in Finland. Given the presence of limited overlap (<3.3%) with the GWAS of inflammatory regulators, investigators considered the risk of bias from sample overlap to be minimal.

The primary analysis used an inverse-variance weighting (IVW) method to assess the causal relationship between inflammatory cytokines and inflammatory arthritis conditions. Other methods, including MR-Egger, weighted median (WM), simple mode, and weighted mode were used to comprehensively evaluate the potential causal relationship. A sensitivity analysis allowed investigators to confirm the robustness of the findings.

Upon analysis, the IVW method revealed elevated levels of macrophage colony-stimulating factor (MCSF) was associated with an increased risk of AS (odds ratio [OR], 1.163 [95% CI, 1.016 - 1.33]; P = .028). On the other hand, higher levels of TRAIL (OR, 0.892 [95% CI, 0.81 - 0.982; P = .002) and beta nerve growth factor (OR, 0.829 [95% CI, 0.696 - 0.988; P = .036) exhibited a decreased risk of AS.

Results from the IVW analysis showed higher levels of 4 inflammatory cytokines were associated with an increased risk of PsA, including VEGF (OR, 1.161 [95% CI, 1.057 - 1.275]; P = .002), interleukin 12p70 (OR, 1.189 [95% CI, 1.049 - 1.346; P = .007), IL-10 (OR, 1.216 [95% CI, 1.024 - 1.444]; P = .026), and IL-13 (OR, 1.159 [95% CI, 1.05 - 1.28]; P = .004). Meanwhile, a high level of interleukin 1 receptor agonist (IL-1rα) was associated with an increased risk of seropositive RA (OR, 1.181 [95% CI, 1.044 - 1.336; P = .008).

Overall, the genetic susceptibility to inflammatory arthritis was causally associated with several inflammatory cytokines. Genetic specialty to AS showed suggestive evidence of increased levels of growth-regulated protein alpha (GRO-α), IL-10, IL-12p70, and TNF-β, while the genetic susceptibility to PsA showed evidence of elevated levels of RANTES, VEGF, and β-NGF and reduced levels of G-CSF and IL-8.

Further analysis revealed the genetic susceptibility of RA was associated with elevated levels of 12 inflammatory cytokines, including IL-1β, monocyte chemoattractant protein 1 (MCP-1), and stem cell growth factor beta (SCGF-β). Liu and colleagues indicated the sensitivity analyses confirmed the robustness of these findings.

“Consequently, future research should focus on validating our findings to gain a better understanding of the relationship between inflammatory cytokines and inflammatory arthritis,” Liu and colleagues wrote.

References

1. _{Pan S, Wu S, Wei Y, Liu J, Zhou C, Chen T, Zhu J, Tan W, Huang C, Feng S, Zhang B, Wei W, Zhan X, Liu C. Exploring the causal relationship between inflammatory cytokines and inflammatory arthritis: A Mendelian randomization study. Cytokine. 2024 Jan;173:156446. doi: 10.1016/j.cyto.2023.156446. Epub 2023 Nov 17. PMID: 37979213.}
2. _{Kim EY, Moudgil KD. Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines. Cytokine. 2017 Oct;98:87-96. doi: 10.1016/j.cyto.2017.04.012. Epub 2017 Apr 25. PMID: 28438552; PMCID: PMC5581685.}
3. _{Xiang M, Wang Y, Gao Z, Wang J, Chen Q, Sun Z, Liang J, Xu J. Exploring causal correlations between inflammatory cytokines and systemic lupus erythematosus: A Mendelian randomization. Front Immunol. 2023 Jan 19;13:985729. doi: 10.3389/fimmu.2022.985729. PMID: 36741410; PMCID: PMC9893779.}