Fetuin-A: A Novel Biomarker of Bone Damage in Early Axial Spondyloarthritis. Results of an Interim Analysis of the SPACE Study

Abstract

Background: Our study aimed to evaluate the association between fetuin-A levels and the presence of radiographic sacroiliitis and syndesmophytes in patients with early axial spondyloarthritis (axSpA) and to identify potential predictors of radiographic damage in the sacroiliac joints (SIJs) after 24 months. Methods: Patients diagnosed with axSpA in the Italian cohort of the SpondyloArthritis-Caught-Early (SPACE) study were included. Physical examinations, laboratory tests (including fetuin-A), SIJ,+ and spinal X-rays and MRIs at T0 (diagnosis) and at T24 were considered. Radiographic damage in the SIJs was defined according to the modified New York criteria (mNY). Results: Fifty-seven patients were included in this analysis (41.2% male, median (interquartile range), chronic back pain [CBP] duration of 12 (8–18) months). Fetuin-A levels were significantly lower in patients with radiographic sacroiliitis compared to those without at T0 (207.9 (181.7–215.9) vs. 239.9 (217.9–286.9), respectively, p < 0.001) and at T24 (207.6 (182.5–246.5) vs. 261.1 (210.2–286.6) µg/mL, p = 0.03). At T0, fetuin-A levels were significantly higher in non-smokers, in patients with heel enthesitis and in those with a family history of axSpA; fetuin-A levels at T24 were higher in females, in patients with higher ESR or CRP at T0 and in those with radiographic sacroiliitis at T0. Fetuin-A levels at T0 were independently negatively associated with the likelihood of radiographic sacroiliitis (OR = 0.9 per 10-unit increase (95% CI 0.8, 0.999), p = 0.048); but not with the presence of syndesmophytes. After adjustment for confounders, fetuin-A levels at T0 and T24 were also negatively associated with mNY at T0 (β −0.5, p < 0.001) and at T24 (β −0.3, p < 0.001), respectively. Among other variables at T0, fetuin-A levels did not achieve statistical significance in predicting mNY at T24. Conclusion: Fetuin-A levels were negatively associated with radiographic damage of the SIJs, but not of the spine, in early axSpA and after 2 years of follow-up. Our findings suggest that fetuin-A levels may serve as a biomarker to identify patients with a higher risk of developing severe disease and early structural damage.

Pathophysiology of Bone and Mineral Metabolism

“…The associations of the genetic prediction of B vitamins and Hcy concentrations with total body BMD and BMD in different age strata are displayed in Figure 4. We observed the significant associations of genetically predicted elevated vitamin B12 with lower total body BMD (Beta, -0.083; 95%CI, -0.126 to -0.040; P = 1.65E-04), especially decreased total body BMD of age [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]95%CI, to -0.067; P = 9.86E-05) and age over 60 years (Beta, -0.074; 95%CI, -0.141 to -0.007; P = 0.031). No significant association was revealed in Hcy and other B vitamins with total body BMD in different age strata (Figure 4, Effects of the genetic prediction of circulating vitamin B12, homocysteine, folate, and vitamin B6 on bone mineral density in different body regions and different age strata with the inverse variance weighting method.…”

“…Additionally, Cochran's Q statistic and the MR-Egger and MR-PRESSO approaches indicated no heterogeneity and no pleiotropy existing in these analyses (Supplementary Tables 6, 7). In the multivariable MR analysis, the genetic prediction of increased vitamin B12 was more significantly associated with lower total body BMD (Beta, -0.085; 95%CI, -0.133, -0.038; P = 4.39E-04), total body BMD of age [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]95%CI,.058; P = 3.55E-04), and age over 60 years (Beta, -0.076; 95% CI, -0.145, -0.008; P = 0.029) after adjusting for education attainment, smoking, and alcohol usage (Supplementary Figure 1). Leave-one-out analysis showed that a single SNP was unable to influence the significant associations, confirming these significant results (Supplementary Figure 2).…”

“…It gives a corrected estimate via removing the outliers and supplies a distortion test, which evaluates whether the calculations with or without outliers obtain similar assessments under the InSIDE assumption (51). We also evaluated Cochran's Q statistic to investigate the magnitude of heterogeneity (53) among the employed SNPs in every analysis. Subsequently, we utilized an online approach to calculate power (Supplementary Table 4) in addition to providing a supporting evidence of the strength of genetic instruments like F-statistics (54).…”

“…There are several mechanisms proposed to explain the increased skeletal fragility in obese individuals such as low vitamin D with consequent secondary hyperparathyroidism (43,44), increased levels of proinflammatory cytokine release from the expanded adipose tissue volume and possibly the high levels of leptin and reduced adiponectin though both have variable effects on the skeleton ( 44) Low vitamin D is easily corrected clinically but the increase in adipose tissue volume and subsequent proinflammatory state requires more effort (45). Likewise, studies (46)(47)(48)(49)(50)(51)(52) have shown that BMD is also higher in patients with T2DM compared to nondiabetic subjects but associated with an increased fracture risk affecting any skeletal site (52,53). Given that obesity is a risk for T2DM, it would be hard to separate out the effect of obesity from diabetes on the bone.…”

Bone metabolism and inflammatory biomarkers in radiographic and non-radiographic axial spondyloarthritis patients: a comprehensive evaluation

“…In this respect, Favero et al. ( 53 ) have suggested that fetuin-A levels could be a useful biomarker for identifying axSpA patients with a high risk of developing severe disease and early structural damage.…”