Greater IL-6 Response After Acute Pain Exposure Among Women With Knee Osteoarthritis

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Investigators assessed sex differences in interleukin-6 response after exposure to acute pain among patients with knee osteoarthritis who were scheduled for total knee arthroplasty.

Compared with men with knee osteoarthritis (OA), women with knee OA show higher interleukin (IL)-6 reactivity in response to acute pain, according to study results published in Journal of Pain. This could explain why women with knee OA experience a more severe perception of pain and are at greater risk of developing chronic pain.

Research also suggests that compared with men with knee OA, women with knee OA experience greater symptom severity. Since IL-6 plays a crucial role in chronic inflammation, central sensitization, and autoimmunity, researchers evaluated whether laboratory-evoked pain produced significant sex differences in inflammatory reactivity among patients with knee OA (n=84; 48 women).

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All patients included in the study received a quantitative sensory testing (QST) battery before they were scheduled for a total knee arthroplasty. A total of 7 measurements of IL-6 were collected: twice at baseline, once immediately after the QST battery, and once every 30 minutes up to 2 hours after QST.

Investigators found a significant time effect, which suggested that overall IL-6 levels among patients with knee OA increased over time after QST (β=0.42±0.04; P <.001). After including a time-squared variable, the fit of the model improved significantly, allowing for nonlinearity [χ(1)=8.97; P <.01]. If the time slope varied across patients, researchers suggested a significant time random slope, indicating that the rate of change across patients varied significantly [χ(1)=213.20; P <.001]. When both sex and time were included in the model, investigators observed a significant sex moderation effect (β=0.04±0.02; P <.05); this effect remained significant even after controlling for clinical pain, body mass index, evoked pain sensitivity, marital status, situational pain catastrophizing, and interaction with time.

The model that included sex effect and time accounted for 64.3% of within-person IL-6 variability (level 1) and 32.5% of between-person IL-6 variability (level 2). When all covariates were included, an additional 3% of level 1 variability and 20% of level 2 variability were explained.

Study limitations included potential entanglement of circadian and pain effects on IL-6 response, a lack of investigation of the full cytokine reactivity cascade, a lack of data on sex hormones, and the potential inability to generalize results according to the homogeneity of the study population.

However, study investigators concluded, “Even after controlling for covariates, women still displayed more pronounced IL-6 reactivity after exposure to laboratory-evoked pain. Given that [knee] OA is a chronic condition, and [patients] with [knee] OA experience pain almost every day, such sex differences in inflammatory response may lead to maintenance or further exacerbation of [knee] OA, especially in women. Future research examining mechanisms contributing to chronic pain and its amelioration need to account for sex as a [biologic] variable to promote the generation of targeted pain interventions.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Mun CJ, Letzen J, Nance S, et al. Sex differences in interleukin-6 responses over time following laboratory pain testing among patients with knee osteoarthritis [published online November 13, 2019]. J Pain. doi:10.1016/j.jpain.2019.11.003