Comment on: Association of serum levels of inflammatory markers and adipokines with joint symptoms and structures in participants with knee osteoarthritis

Dear Editor, The recent publication by Zhu and colleagues [1] provides compelling results and interpretation regarding the association of circulating inflammatory markers and adipokines with joint symptoms and structures in knee osteoarthritis. The post hoc analysis from a randomized, double blind, placebo-controlled study examined 19 serum inflammatory biomarkers, joint symptoms and joint structures at baseline and 24 months later in 200 subjects with symptomatic and imaging evidence of knee osteoarthritis. Joint symptoms were assessed using the Western Ontario and McMaster Universities Index and magnetic resonance imaging was used to determine joint structures. A principal component analysis was initially performed to identify interrelated biomarker clusters and generalized estimating equations were subsequently implemented to associate the principal components with knee symptoms and structures.

From the serum inflammatory and adipokine biomarkers investigated, Zhu and colleagues [1] were able to identify five interrelated components (i.e. pro-inflammatory cytokine, IL-10-related anti-inflammatory, CRP-related metabolic inflammation, resistin-related metabolic inflammation and adiponectin-related metabolic inflammation) that associated with joint symptoms and structures in knee osteoarthritis. Those novel findings extend previous principal component analysis research conducted in subjects with osteoarthritis [2, 3] and other research that has predominately relied on associating individual biomarkers in the blood with osteoarthritis symptoms, onset and/or progression. The unique findings by Zhu and colleagues [1] also allude to a couple of topics needed to advance future biomarker research in osteoarthritis, and therefore are worthy of additional discussion.

As mentioned therein, Zhu and colleagues [1] utilized standard criteria in the diagnosis of knee osteoarthritis and eloquently report the clinical symptoms and knee joint structure data at baseline and month 24. Unfortunately, it is unclear if the study consisted exclusively of subjects with unilateral or bilateral knee osteoarthritis and disease severity was not provided. Differences in disease severity upon enrolment and including a mixture of unilateral and bilateral knee osteoarthritic subjects in the analysis could impact circulating biomarker concentrations, and without appropriate statistical adjustments or controls, confound the study results. With that said, however, the findings therein [1] could be more generalizable to a broader patient population if the composition of study cohort was not limited to subjects with either unilateral or bilateral knee osteoarthritis. Also, analyses linking the interrelated principal components to disease severity and disease progression would be opportunistic in establishing biomarker-based phenotypes of osteoarthritis that associate with disease trajectories. Such analyses are sparse in the literature.

Supplemental vitamin D was ineffective at altering circulating inflammatory biomarkers and statistical analyses were adjusted for serum 25-hydroxyvitamin D concentrations, as described [1, 4]. To extend their earlier findings [4], those most recently [1] and the general knowledge in this field of research, it would be of interest to identify if component clustering and clustering associations with clinical variables are different between subjects that were randomized to the vitamin D compared with the placebo supplement. Considering the reciprocal regulation between diverse cytokines and the cytokine modulating property of vitamin D, such aforementioned analyses would provide new evidence regarding the ability of supplemental vitamin D to alter: (i) the interrelationship between mutually regulated cytokines and (ii) the principal components (i.e. interrelated biomarker clusters) associations with osteoarthritis symptoms and structural features in the absence of individual biomarker perturbations.

The study by Zhu and colleagues [1] provides unique data relating biomarker clusters to clinical symptoms and joint structures in knee osteoarthritis. Those findings [1] extend the current knowledge and add to the rationale for large proteomic and metabolomic research in osteoarthritis. Large biomarker dataset studies will be instrumental in delineating the various phenotypes and endophenotypes of knee osteoarthritis necessary to improve precision medicine efforts and to assist the clinical decision process of healthcare delivery in patients suffering with knee osteoarthritis.

Funding statement: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement: The author has declared no conflicts of interest.

Data availability statement

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.

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