Background: Inflammation in axial spondyloarthritis (axSpA) can result in structural damage to the axial skeleton, leading to restricted spinal mobility. The progression of this damage is unpredictable, occurring in both early and advanced stages of the disease. Additionally, axSpA is marked by dysregulated bone metabolism, with an imbalance between bone formation and resorption driving structural changes and further contributing to disease progression. Understanding the molecular mechanisms underlying these processes is therefore crucial to advancing knowledge and improving patient outcomes.

Objectives: 1) To identify axSpA patients with a phenotype of persistent systemic inflammation and investigate its association with structural damage, radiographic progression, and bone-related parameters; 2) to elucidate the proteomic profile associated with persistent systemic inflammation and identify potential bone dysregulators driving disease progression and 3) to analyze the impact of axSpA, driven by systemic inflammation phenotypes, on an osteoblast cell line.

Methods: A longitudinal retrospective study was conducted involving 250 axSpA patients. Systemic inflammation was evaluated by analyzing persistently elevated C-reactive protein (CRP) levels sustained over a five-year period prior to the rheumatology consultation. CRP levels above 5 mg/L were considered indicative of active inflammation, with at least one CRP measurement taken per year for each patient. Patients were classified into three groups based on the proportion of CRP measurements exceeding the 5 mg/L threshold: 1) Persistent systemic inflammation (more than 85% of CRP measurements >5 mg/L); 2) Intermittent systemic inflammation (CRP measurements >5 mg/L between 25-85% of the time); and 3) No persistent systemic inflammation (less than 25% of CRP measurements >5 mg/L). Clinical and laboratory parameters were recorded, structural damage was evaluated using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS), and disease progression was assessed by calculating the change in mSASSS over a five-year follow-up period. A total of 184 proteins were measured using Olink technology. Additionally, an osteoblast cell line (UMR-106) was treated with serum from patients representing different systemic inflammation phenotypes to evaluate the impact of the disease on bone metabolism.

Results: AxSpA patients with persistent systemic inflammation were predominantly male, HLA-B27 positive, and exhibited significantly higher disease activity, alkaline phosphatase, parathyroid hormone, and calcium. These patients also had higher total and lumbar mSASSS scores, a greater presence of syndesmophytes, and a higher proportion of radiographic sacroiliitis. Additionally, they showed a greater progression of structural damage, as indicated by changes in mSASSS over a five-year follow-up, compared to patients with intermittent or no systemic inflammation. The molecular characterization of distinct systemic inflammation phenotypes revealed significant alterations in 17 proteins after FDR adjustment, including several directly implicated in bone metabolism, such as RANKL, CSF-1, OPG, IL-6, C3, MMP-1, and MMP-9. These proteins were significantly upregulated in patients with axSpA and persistent systemic inflammation compared to those with intermittent or no persistent systemic inflammation, indicating a dysregulation in bone formation and resorption. Notably, IL-6 and CDCP-1 levels showed a positive correlation with total mSASSS, the presence of syndesmophytes, and bone bridges. To further explore this, we evaluated the specific impact of CDCP-1 on osteoblasts. Increasing doses of CDCP-1 led to elevated expression of IL-6, ICAM, and FGF-23, while simultaneously reducing the expression of ALP, DMP-1, pPHEX, and SOST compared to controls. These findings suggest that CDCP-1 disrupts normal osteoblast function by activating inflammatory pathways and suppressing key markers of bone formation and mineralization. Additionally, we examined the effect of serum from axSpA patients with persistent systemic inflammation on an osteoblast cell line. Serum from these patients significantly increased the expression of IL-6, ALP, and ICAM, while reducing the expression of DMP-1, BMP-2, pPHEX, FGF-23, and SOST. These results indicate that the specific inflammatory environment in axSpA with prolonged chronic inflammation promotes a heightened inflammatory state and increases markers of bone remodeling. However, this process also disrupts bone formation and mineralization, leading to dysregulated bone remodeling and impaired bone quality.

Conclusion: 1) AxSpA patients with persistent systemic inflammation are predominantly male, HLA-B27 positive, have elevated bone turnover, and show greater progression of structural damage; 2) the molecular background of proteins related to bone formation and resorption is associated with different systemic inflammation phenotypes; 3) CDCP-1 is strongly associated with structural damage and disrupts osteoblast function, contributing to impaired bone metabolism; 4) serum from axSpA patients with persistent systemic inflammation induces an inflammatory state, increases bone remodeling markers, and reduces bone formation in osteoblast cell line. Thus, chronic inflammation in axSpA drives dysregulated bone remodeling and progressive structural damage, highlighting potential molecular targets for therapeutic strategies.

REFERENCES: NIL.

Acknowledgements: Project “PMP21/00119”, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.