Levels of Peripheral Th17 Cells and Th17-Related Cytokines in Patients with Ankylosing Spondylitis: A Meta-analysis

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.

Keywords: Ankylosing spondylitis; IL-17; IL-21; IL-23; Th17.