The relationship between circulating and tissue biomarkers and OA-related pain: A systematic literature review

Abstract

Objective: This study aimed to provide an overview of the relationship between osteoarthritis (OA) pain and various fluid biomarkers by conducting a systematic literature review (SLR), to help the development of OA-related pain endotyping. Method: An SLR was conducted, using the PubMed, Embase, Scopus, Web of Science and the Cochrane Library databases, up to December 2024. Pain measures (VAS, WOMAC, HOOS/KOOS, AUSCAN, PainDETECT and Pain Pressure Threshold) were analysed for their association with circulating biomarkers in blood, urine, synovial and cerebrospinal fluids or tissue and genetic biomarkers. Biomarkers were categorised as “associated” depending on statistical significance and further subcategorised as “consistently associated”, “uncertainly associated” or “not associated” based on the quality of evidence determined by the number of studies, sample size and the strength of correlation. Results: The five databases yielded 30,088 citations, of which 263 relevant papers were selected. Total cholesterol in the blood was the only biomarker consistently associated with pain. Among blood biomarkers, CRP, hsCRP and IL-17 showed suggestive but inconsistent associations with OA-related pain. In synovial fluid, IL-17, C2C and VEGF were consistently associated with increasing pain intensity, based on multiple concordant studies. In cerebrospinal fluid, CX3CL1 and Flt-1 were consistently associated with pain, displaying a negative correlation. Conclusion: This SLR identified no relevant biomarkers in different body fluids that were associated with OA-related pain. Further investigation of CRP and IL-17 is required to achieve greater consistency across studies. PROSPERO: CRD42024550244.