Inflammatory Processes Contribute to Chronic Back Pain and Musculoskeletal Comorbidities

A Mendelian randomization analysis found evidence to suggest that chronic back pain and musculoskeletal comorbidities arise from similar age-related inflammatory processes, according to the results of a study published in Pain.

The CHARGE Inflammation Working Group sourced data for this study from the UK Biobank. Whole genome sequences from 422,863 individuals were evaluated for genetic correlations using a Mendelian randomization approach to identify causal relationships between the musculoskeletal phenotypes of rheumatoid arthritis (n=4883), osteoporosis (n=7153), bone mineral density of the calcaneus (BMD; n=242,216), and chronic back pain (n=73,794).

The mean age of the study population was 57.34 (range, 39.70-73.70) years; 17.95% had chronic back pain, 1.69% had osteoporosis, and 1.15% had rheumatoid arthritis. However, the incidence of osteoporosis and rheumatoid arthritis among participants with chronic back pain was significantly increased at 30.77% and 29.79%, respectively.

In multiple logistic regression analysis, chronic back pain was significantly related with rheumatoid arthritis (β, 0.5707; P <2.00E^-16), osteoporosis (β, 0.7711; P <2.00E^-16), C reactive protein (β, 0.0606; P <2.00E^-16), BMI (β, 0.2280; P <2.00E^-16), age (β, 0.0211; P =6.52E^-7), and sex (β, -0.0409; P <1.43E^-6).

Genetic correlations calculated using linkage disequilibrium score regression were observed between chronic back pain and BMI (Rg, 0.3461; P =9.64E^-65), C-reactive protein (Rg, 0.2548; P =6.25E^-10), rheumatoid arthritis (Rg, 0.4194; P =6.06E^-7), osteoporosis (Rg, 0.0421; P =3.86E^-1), and calcaneal BMD (Rg, 0.0053; P =7.75E^-1).

In the Mendelian randomization analysis using the inverse-variance weighted approach, chronic back pain was related with BMI (β, 0.338; 95% CI, 0.304-0.372; P <.001), C-reactive protein (β, 0.234; 95% CI, 0.167-0.301; P <.001), rheumatoid arthritis (β, 0.022; 95% CI, 0.014-0.30; P <.001), and calcaneal BMD (β, -0.155; 95% CI, -0.179 to -0.131; P <.001). Similar findings were observed using weighted Mendelian randomization and the Mendelian randomization PRESSO method. Using a weighted mode approach, only C-reactive protein (P <.001), rheumatoid arthritis (P =.005), and calcaneal BMD (P =.013) were significant. Using a Mendelian randomization-Egger approach, only BMI (P <.001), rheumatoid arthritis (P <.001), and calcaneal BMD (P <.001) were significant.

Chronic back pain had 8 significant causal genetic regions in common with BMI, 7 genetic regions in common with rheumatoid arthritis, 6 genetic regions in common with C-reactive protein, and 10 genetic regions in common with calcaneal BMD.

In the additive Bayesian network analysis, aging played a central role in the relationships. Increased BMI (β, 0.20) and C-reactive protein led to systemic inflammation (β, 0.010), contributing to chronic back pain. This systemic inflammation was also dependent on the presence of rheumatoid arthritis (β, 0.56) and osteoporosis (β, 0.82). C-reactive protein indirectly contributed to chronic back pain via rheumatoid arthritis (β, 0.54) and BMD (β, -0.03). Decreased calcaneal BMD also influenced rheumatoid arthritis (β, -0.19) and osteoporosis (β, -0.84).

A major limitation of this study was the use of a back pain meta-analyzed genome-wide association study to define chronic back pain.

This study found that there may be a common pathophysiology between chronic back pain and musculoskeletal comorbidities mediated by inflammation, as measured by C-reactive protein. The musculoskeletal comorbidities tended to be observed among aging populations; therefore, inflammation with age may be a pathway leading to these phenotypes. “While the exact mechanism has yet to be identified, several key genes appeared to be involved in the development of [chronic back pain] as well as linked to inflammation, as well as [rheumatoid arthritis and bone deterioration, and may possibly be key therapeutic targets in addressing [chronic back pain,” the researchers concluded.