Authors: Qin-Yi Su, Jing-Wen Zheng, Jing-Yuan Yang, Tong-Yuan Zhang, Shan Song, Rong Zhao, Jing-Kai Di, Sheng-Xiao Zhang, Cai-Hong Wang & Hui-Ying Gao
Abstract
Background
Ankylosing spondylitis (AS) is a chronic inflammatory disease. Several proinflammatory cytokines produced by T helper 17 (Th17) cells are involved in the pathogenesis of AS. We performed a meta-analysis to determine the levels of Th17 cells and serum Th17-associated cytokines in patients with AS.
Methods
We determined the levels of Th17 cells and Th17 cytokines in patients with AS using data extracted from published articles retrieved from the PubMed, Embase, Web of Science, Cochrane Library, MEDLINE, Web of Knowledge, Clinical Trials.gov, and FDA.gov. databases. The effect estimates were pooled using a random-effects model. The review protocols were registered on PROSPERO (reference: CRD42021255741) and followed the PRISMA guideline.
Results
This meta-analysis included 138 studies. Compared to healthy controls (HCs), patients with AS had a higher proportion of Th17 cells (standardized mean difference [SMD] 2.23, 95% confidence interval [CI] 1.78–2.68; p < 0.001) and levels of proinflammatory cytokines, such as interleukin (IL)-17 (SMD 2.04, 95% CI 1.70–2.38; p < 0.001), IL-21 (SMD 1.77, 95% CI 0.95–2.59; p < 0.001), and IL-23 (SMD 1.11, 95% CI 0.78–1.44; p < 0.001). The subgroup analysis showed higher levels of IL-17+ Th17 cells among peripheral blood mononuclear cells (PBMCs) and CD4+ T cells in patients with AS compared to HCs (SMD 2.26, 95% CI 1.58–2.94 [p < 0.001] and SMD 1.61, 95% CI 0.55–2.67 [p = 0.003], respectively). Patients with AS had higher levels of CD4+IL-17+IFN-γ− Th17 in PBMCs and of CD4+CCR6+CCR4+Th17 in CD4+ T cells compared to HCs (SMD 1.85, 95% CI 1.06–2.64 [p < 0.001] and SMD 7.72, 95% CI 6.55–8.89 [p < 0.001], respectively). No significant differences were observed in the proportions of CD4+IL-17+IFN-γ− Th17 in CD4+ T cells and CD4+CCR6+CCR4+ Th17 in PBMCs (SMD − 0.11, 95% CI − 0.61 to 0.38 [p = 0.650] and SMD 1.32, 95% CI − 0.54 to 3.19 [p = 0.165], respectively). In addition, compared to stable AS, the levels of Th17 cells and IL-17 and IL-23 were significantly higher in active AS (SMD 1.58, 95% CI 0.30–2.85 [p = 0.016], SMD 3.52, 95% CI 0.72–6.33 [p = 0.014], and SMD 5.10, 95% CI 1.83–8.36 [p = 0.002], respectively).
Conclusions
The levels of Th17 cells and serum IL-17, IL-21, and IL-23 were higher in patients with AS than in HCs and, compared with stable AS, they increased more significantly in active AS. These results suggest that Th17 cells and Th17-related cytokines play major roles in AS pathogenesis and are an important target for treatment.
Key Summary Points |
The levels of T helper 17 (Th17) cells and serum interleukin (IL)-17, IL-21 and IL-23 were higher in patients with ankylosing spondylitis (AS) than in healthy controls. |
The levels of Th17 cells and serum IL-17 and IL-23 were higher in active AS than in stable AS. |
Patients with AS had higher proportions of CD4+IL-17+ Th17 cells, CD4+IL-17A+ Th17 cells, and CD4+CCR6+CCR4+ Th17 cells than healthy controls. |
Th17 cells marked by “CD4+IL-17+IFN-γ−” and “CD4+IL-17+IFN-γ−IL-22+” were significantly higher in the peripheral blood mononuclear cells of patients with AS than in those of healthy controls, but not in CD4+ T cells. |
Although trials of IL-23 inhibitors for the treatment of AS have failed to show benefit, the IL-17/IL-23 axis plays an important role in the onset and progression of AS; therefore, the IL-17/IL-23 axis may be targeted for AS treatment. |