Plasma Pro- and Anti-Inflammatory Cytokines in an Observational Chronic Low Back Pain Cohort

Abstract

Background: Chronic low back pain (cLBP) is a multifactorial condition that can have various contributing factors, including biological, biomechanical, and behavioral. Recent evidence suggests that systemic inflammation may contribute to cLBP, impacting pain sensitivity and individuals' functional status. Circulatory pro- and anti-inflammatory cytokines are widely used to determine individuals' systemic inflammatory status. The University of Pittsburgh Mechanistic Research Center, part of the National Institutes of Health's (NIH) Helping to End Addiction Long-term Initiative, conducted a prospective, observational study to identify phenotypes in a large cohort of individuals with cLBP. The present work reports the quantification of key circulatory cytokines in this cLBP cohort.

Methods: A total of 1007 individuals with cLBP were enrolled. Plasma samples were available from 936 participants, and concentrations of pro-inflammatory (IL-6, IFN-γ, TNF, IL-15, Leptin) and anti-inflammatory (IL-1ra, IL-10) cytokines were measured via immunoassays. Pain and functional status were assessed using validated self-reported numeric pain ratings scale and the Oswestry Disability Index. Descriptive statistics of analyzed cytokines were reported across the overall population, stratified by age (< 60 and ≥ 60 years old) and sex, and by pain levels as mild (0-5), moderate (6, 7), and severe (8-10), and ODI, categorized as minimal disability (0%-20%), moderate (21%-40%), and severe disability (> 40%).

Results: The values of circulating cytokines assessed in this study aligned with those reported in the literature for other painful inflammatory conditions and, in most cases, exceeded those documented for healthy populations. IL-6, IL-1ra, and Leptin demonstrated higher concentrations with higher pain and disability severity. TNF showed higher concentration in participants with higher disability severity. Concentration levels of IFN-γ, IL-15, and IL-10 exhibited no differences across pain or ODI categories. Notably, TNF levels were higher in older adults (≥ 60 years), whereas Leptin levels were higher in females than in males.

Conclusion: This study provides a snapshot of key circulating cytokines in a large cLBP cohort, revealing differences in pro- and anti-inflammatory cytokines across pain and disability for the overall population and in sex and age subgroups. Additional longitudinal and mechanistic studies are required to clarify how cytokines could serve as diagnostic, prognostic, or phenotyping markers, ultimately informing targeted, inflammation-focused therapies that may reshape current treatment approaches.

Keywords: anti‐inflammatory cytokines; chronic low back pain (cLBP); inflammatory cytokines; plasma protein biomarkers.

FIGURE 1

Distribution of Pro‐Inflammatory cytokines across Pain and ODI categories. Each panel shows box‐and‐whisker plots of cytokine levels (TNF, IL‐15, Leptin, IFN‐γ) across three categories of pain (in blue; mild, moderate, severe) and three categories of disability (in red; mild, moderate, severe, per the Oswestry Disability Index [ODI]). The box boundaries represent the 25th and 75th percentiles, the horizontal line within each box is the median, and the whiskers extend to the minimum and maximum values (excluding outliers). Numeric annotations (e.g., mean, median, min, max) are displayed above each group.

FIGURE 2

Distribution of Anti‐Inflammatory cytokines across Pain and ODI categories. Each panel shows box‐and‐whisker plots of cytokine levels (IL‐10, IL‐6, IL‐1ra) across three categories of pain (in blue; mild, moderate, severe) and three categories of disability (in red; mild, moderate, severe, per the Oswestry Disability Index [ODI]). The box boundaries represent the 25th and 75th percentiles, the horizontal line within each box is the median, and the whiskers extend to the minimum and maximum values (excluding outliers). Numeric annotations (e.g., mean, median, min, max) are displayed above each group.