BACKGROUND: Interleukin 40 (IL-40) is a newly identified B cell-associated cytokine implicated in humoral immune responses and B cell homeostasis. As B cells play a pivotal role in autoimmunity, we investigated the function of IL-40 in rheumatoid arthritis (RA). METHODS: IL-40 expression was determined in the synovial tissue from RA and osteoarthritis (OA) patients. IL-40 was analysed in the serum/synovial fluid of patients with RA (n=50), systemic lupus erythematosus (SLE, n=69), OA (n=44), and healthy controls (HC, n=50). We assessed the changes of IL-40 levels in RA patients following the B cell depletion by rituximab (n=29) or after the TNF inhibition by adalimumab (n=25). We examined the relationship between IL-40, disease activity, autoantibodies, cytokines, and NETosis markers. Effect of IL-40 on synovial fibroblasts was determined. RESULTS: IL-40 was overexpressed in RA synovial tissue, particularly by synovial lining and infiltrating immune cells. The levels of IL-40 were up-regulated in the synovial fluid of RA versus OA patients (p<0.0001). Similarly, IL-40 was increased in the serum of RA patients compared to HC, OA, or SLE (p<0.0001 for all) and decreased after 16 and 24 weeks (p<0.01 and p<0.01) following rituximab treatment. No significant effect of adalimumab on IL-40 was observed. IL-40 levels in RA patients correlated with rheumatoid factor-IgM and anti-cyclic citrullinated peptides (anti-CCP) in the serum (p<0.0001 and p<0.01), as well as in the synovial fluid (p<0.0001 and p<0.001). Synovial fluid IL-40 was also associated with disease activity score DAS28 (p<0.05), synovial fluid leukocyte count (p<0.01), neutrophil attractants IL-8 (p<0.01), MIP-1α (p<0.01), and markers of neutrophil extracellular traps externalization (NETosis) such as proteinase 3 (p<0.0001) and neutrophil elastase (p<0.0001). Synovial fibroblasts exposed to IL-40 increased the secretion of IL-8 (p<0.01), MCP-1 (p<0.05), and MMP-13 (p<0.01) compared to the unstimulated cells. CONCLUSIONS: We show the up-regulation of IL-40 in RA and its decrease following B cell depleting therapy. The association of IL-40 with autoantibodies, chemokines, and markers of NETosis may imply its potential involvement in RA development. Moreover, IL-40 up-regulates the secretion of chemokines and MMP-13 in synovial fibroblasts, indicating its role in the regulation of inflammation and tissue destruction in RA.
- Keywords
- B cells, NETosis, autoantibodies, disease activity, interleukin-40, rheumatoid arthritis,
- MeSH
- Adalimumab therapeutic use MeSH
- Antirheumatic Agents pharmacology therapeutic use MeSH
- Osteoarthritis, Knee immunology metabolism MeSH
- Autoantibodies blood MeSH
- B-Lymphocytes drug effects immunology MeSH
- Biomarkers MeSH
- Cytokines analysis MeSH
- Adult MeSH
- Extracellular Traps immunology MeSH
- Fibroblasts MeSH
- Interleukins metabolism MeSH
- Cohort Studies MeSH
- Cells, Cultured MeSH
- Middle Aged MeSH
- Humans MeSH
- Lymphocyte Depletion MeSH
- Matrix Metalloproteinase 13 analysis MeSH
- Gene Expression Regulation drug effects MeSH
- Arthritis, Rheumatoid immunology therapy MeSH
- Rituximab pharmacology therapeutic use MeSH
- Aged MeSH
- Synovial Membrane chemistry immunology MeSH
- Synovial Fluid chemistry immunology MeSH
- Lupus Erythematosus, Systemic immunology metabolism MeSH
- Tumor Necrosis Factor-alpha antagonists & inhibitors MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Adalimumab MeSH
- Antirheumatic Agents MeSH
- Autoantibodies MeSH
- Biomarkers MeSH
- C17orf99 protein, human MeSH Browser
- Cytokines MeSH
- Interleukins MeSH
- Matrix Metalloproteinase 13 MeSH
- Rituximab MeSH
- Tumor Necrosis Factor-alpha MeSH
OBJECTIVE: To evaluate circulating visfatin and its relationship with disease activity and serum lipids in patients with early, treatment-naïve rheumatoid arthritis (RA). METHODS: Serum visfatin was measured in 40 patients with early RA before and after three months of treatment and in 30 age- and sex-matched healthy individuals. Disease activity was assessed using the Disease Activity Score for 28 joints (DAS28) at baseline and at three and 12 months. Multivariate linear regression analysis was performed to evaluate whether improved disease activity is related to serum visfatin or a change in visfatin level. RESULTS: Serum visfatin was significantly elevated in early RA patients compared to healthy controls (1.92±1.17 vs. 1.36±0.93 ng/ml; p = 0.034) and significantly decreased after three months of treatment (to 0.99±0.67 ng/ml; p<0.001). Circulating visfatin and a change in visfatin level correlated with disease activity and improved disease activity over time, respectively. A decrease in visfatin after three months predicted a DAS28 improvement after 12 months. In addition, decreased serum visfatin was not associated with an improved atherogenic index but was associated with an increase in total cholesterol level. CONCLUSION: A short-term decrease in circulating visfatin may represent an independent predictor of long-term disease activity improvement in patients with early RA.
- MeSH
- Antirheumatic Agents therapeutic use MeSH
- C-Reactive Protein metabolism MeSH
- Time Factors MeSH
- Cholesterol blood MeSH
- Adult MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Linear Models MeSH
- Lipids blood MeSH
- Multivariate Analysis MeSH
- Nicotinamide Phosphoribosyltransferase blood MeSH
- Arthritis, Rheumatoid blood drug therapy pathology MeSH
- Aged MeSH
- Severity of Illness Index MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antirheumatic Agents MeSH
- C-Reactive Protein MeSH
- Cholesterol MeSH
- Lipids MeSH
- Nicotinamide Phosphoribosyltransferase MeSH
