Differential association of inflammation with pain and physical function in knee osteoarthritis by race: Focusing on non-Hispanic Whites and Asian Americans

doi:10.21203/rs.3.rs-5228312/v1

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Differential association of inflammation with pain and physical function in knee osteoarthritis by race: Focusing on non-Hispanic Whites and Asian Americans

https://doi.org/10.21203/rs.3.rs-5228312/v1

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Background: The current body of work has not yet addressed the potential racial differences in the relationship between systemic inflammation and knee osteoarthritis (OA) symptoms, including pain and physical function. This pilot study aimed to investigate this association specifically among non-Hispanic Whites (NHWs) and Asian Americans.

Design: We cross-sectionally analyzed 40 community-dwelling participants aged 50–70 years with self-reported knee OA pain, including 20 NHWs and 20 Asian Americans. Knee OA symptoms were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and functional subscales. The serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-10, as systemic inflammatory markers, were measured. Univariate and multivariable analyses, using stepwise linear regression models, were conducted to examine the correlation between these inflammatory markers and OA symptoms, with systematic adjustment for age.

Results: In NHWs, the above inflammatory markers did not correlate with knee pain or physical function. In Asian Americans, bivariate analyses revealed that CRP and TNF-α were associated with worse WOMAC pain scores (r = 1.325, p = .041; r = 2.418, p= .036, respectively), and CRP was also linked to worse WOMAC functional scores (r = 4.950, p = .035). Multivariate analyses confirmed the association of CRP with both worse WOMAC pain (β = 1.328, p = .046) and functional (β = 4.974, p = .034) scores in this group.

Conclusions: CRP may be a clinically relevant marker for knee OA symptoms, specifically in Asian Americans; however, caution is warranted owing to the exploratory nature of this study. Future research is set to benefit from leveraging a larger sample, incorporating additional inflammatory markers, and including racially diverse samples to validate and augment these findings.

Asian Americans

inflammation

knee osteoarthritis

pain

physical

Knee osteoarthritis (OA) is one of the leading causes of pain, daily living impairments, and disability in people aged ≥ 45 years. Although local inflammation aggravates OA joint pathologies, systemic inflammatory markers are also elevated in OA, especially in the presence of symptoms such as pain and reduced functional function (Berenbaum, 2013; Jin et al., 2015). Notwithstanding, the evidence remains controversial. The pooled results of a meta-analysis indicated a weak correlation between serum C-reactive protein (CRP) levels and OA knee pain (Jin et al., 2015). Other studies have identified no significant association between serum CRP levels and knee OA pain or physical function (Penninx et al., 2004; Stürmer et al., 2004). A recent systematic review also reported conflicting associations of other markers, such as interleukin (IL)-6, with pain scores in patients with knee OA (Dainese et al., 2022). Several researchers argue that inconsistent evidence regarding the relationship between inflammation and knee OA symptoms is attributable to sex-specific differences (Kaarvatn et al., 2013; Perruccio et al., 2017; Perruccio et al., 2019). However, considerably less attention has been focused on the possibility of racial/ethnic disparities in these relationships. Racial/ethnic minority groups, owing to systemic inequities and environmental challenges, may develop a different inflammatory fingerprint than their non-Hispanic White (NHW) counterparts (i.e., epigenetics) (Aroke et al., 2019). They are also disproportionately susceptible to chronic knee OA pain (Ahn et al., 2017a; Quintero et al., 2024; Vaughn et al., 2019). Nonetheless, most studies on inflammation and knee OA symptoms have failed to specify the racial composition of their samples, predominantly included NHW participants, or adopted typical approaches that report average effects from race/ethnicity-adjusted analyses, possibly obscuring crucial dissimilarities. Overlooking such differences potentially hinders the development of personalized approaches to analgesic care and interventions that improve physical function, ultimately impeding efforts to reduce pain inequities across groups. To our knowledge, no study has elucidated the potential racial/ethnic differences in the relationship between systemic inflammatory markers and knee OA symptoms. Only recently, Overstreet et al. (2024) found that the expressions/profiles of biomarkers underlying inflammation associated with chronic low back pain-related outcomes (i.e., pain interference, pain at rest, and movement-evoked pain) differed between NHWs and non-Hispanic Blacks. Aim of the Study This pilot study investigated the relationship between inflammation and knee OA symptoms (i.e., pain and physical function) by race. Specifically, we compared NHWs to Asian Americans. Asian Americans constitute a rapidly growing minority yet have been underrepresented in knee OA research, despite emerging evidence indicating that they experience greater knee OA symptoms than NHWs (Ahn et al., 2017b). This underscores the critical importance of studying this population.

Study Participants

This cross-sectional analysis used baseline data from a randomized controlled trial registered at clinicaltrials.gov (NCT02512393) to assess the efficacy of transcranial direct current stimulation (tDCS) in mitigating knee OA pain. Detailed selection criteria and enrollment procedures have been described previously (Ahn et al., 2017b). In brief, at baseline, 40 participants with self-reported knee OA pain (20 NHWs and 20 Asian Americans) were recruited in North Central Florida between September 2015 and August 2016 through local advertisements. Participants were eligible if aged 50–70, if they reported unilateral or bilateral knee OA pain according to American College of Rheumatology criteria, were able to speak and read English, and were willing and able to provide written informed consent before enrollment.

Exclusion criteria ensured that participants did not have concurrent medical conditions that could confound OA-related outcomes or coexisting diseases that could hinder protocol completion. Thus, the following were the exclusion criteria: (1) having undergone prosthetic knee replacement or non-arthroscopic surgery on the affected knee, (2) a serious medical illness, such as uncontrolled hypertension, heart failure, or a recent history of acute myocardial infarction, (3) peripheral neuropathy, (4) systemic rheumatic disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia, (5) alcohol or substance abuse, (6) cognitive impairment, defined as a Mini-Mental Status Exam score of 23 or lower, (7) a history of brain surgery, tumor, seizure, stroke, or intracranial metal implantation, (8) pregnancy or lactation, and (9) hospitalization for a psychiatric illness within the past year.

Measurement

Knee OA Symptoms: Knee OA pain and physical function

Knee OA pain and physical function were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and functional subscales, where higher scores indicate greater pain and physical functional disability (Bellamy et al., 1988). The pain subscale includes 5 items on a 5-point Likert scale (0 being none to 4 being extreme) measuring the pain severity during walking, climbing stairs, sleeping, resting, and standing. The participants’ responses to the pain questions were summed up to derive an aggregated score of pain intensity (range 0–20). The functional subscale asks patients to rate the degree of difficulty in accomplishing 17 activities of daily living on a 5-point scale (0 being none to 4 being extreme). The participants’ responses were aggregated to produce a composite score of functional disability (range 0–68). The subscales in WOMAC demonstrate reliability and validity in evaluating knee OA patients (Bellamy & Buchanan, 1986; Roos et al., 1999).

Inflammatory Markers

In this study, we also gathered data regarding the following inflammatory markers: CRP, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-6, and IL-10. Owing to excessively missing data (45.0%–80.0%), we excluded IL-1β and IL-6 from the current analysis. In the original study (blinded for review), blood samples were obtained prior to treatment initiation (i.e., tDCS) on Day 1 and again after the completing the fifth treatment on Day 5. For our analysis, we utilized pre-treatment data acquired on Day 1. Blood was drawn into ethylenediaminetetraacetic acid plasma tubes. Samples were inverted five times and stored on ice until further processing. Within 30 min of being collected, samples were centrifuged at 1,600 × g and 4 ºC for 15 min, aliquoted, and immediately stored in a −80 ºC freezer.

The plasma samples underwent solid-phase extraction using an Oasis™ Hydrophilic–Lipophilic-Balanced (30 mg) 96-well plate along with a vacuum manifold (Waters Corp., Milford, MA, USA), according to the manufacturer’s protocol. Briefly, the plate was conditioned with acetonitrile and equilibrated twice with 0.1% trifluoroacetic acid (TFA) in high-performance liquid chromatography (HPLC)-grade water. Samples were acidified with 1% TFA (1:1) and loaded onto the plate. The plate was washed thrice with 0.1% TFA in HPLC-grade water. The samples were eluted in 60% acetonitrile/40% HPLC-grade water/0.1% TFA and dried in a Savant AES1010 Automatic Environmental SpeedVAC® w/VaporNet Radiant Cover. Thereafter, they were reconstituted using the original sample volume in assay buffer.

Plasma CRP levels were measured in duplicate using enzyme-linked immunosorbent assays, following the manufacturers’ instructions (cat# DCRP00, R&D Systems, Minneapolis, MN; cat# ADI-900-071, Enzo Life Sciences, Inc., Farmingdale, NY, respectively). For CRP, the average intra- and interassay CV values were < 10.0% and < 7.0%, respectively. TNF-α and IL-10 plasma levels were measured in triplicate using a commercial multiplex immunoassay kit (cat# HCYTMAG-60Kl; MilliporeSigma, Burlington, MA) and analyzed using the MILLIPLEX® Analyzer 3.1 xPONENT® System. Data acquisition was accomplished using the same system and data analysis performed via MILLIPLEX® Analyst Software. Intra- and interassay CVs were < 19.0% for all markers.

Statistical Analysis

Descriptive and comparative statistics were employed to determine sample characteristics. As the inflammatory markers were not normally distributed, log transformation was applied to mitigate skewness. When missing data were present (CRP, n = 4), listwise deletion was performed, resulting in a streamlined dataset for analysis. Race-stratified analyses were conducted owing to an observed interaction between race and certain inflammatory markers, such as CRP (data not shown). We examined the relationships between body mass index (BMI) and each inflammatory marker, aiming to circumvent possible collinearity (since adiposity proves to be significantly associated with systemic inflammation), and specifically investigated their associations with knee OA symptoms. Multivariable linear regression models were used in the main analysis of each outcome.

Explanatory variables included age, sex (male vs. female), marital status (partnered vs. unpartnered), BMI (kg/m²), and Kellgren–Lawrence (KL) radiographic grade (0–1 vs. 2–4), all of which potentially affect both inflammation and knee OA symptoms (Hunter et al., 2008; Heidari et al., 2016). Pain catastrophizing and negative affect were also considered because of their potential relation to widespread pain (Dave et al., 2015; Finan et al., 2013). Candidate variables comprised those with p < .200 in bivariate analyses: single-factor analysis of variance in cases of variance equality, the Kruskal–Wallis test for qualitative variables, and the simple linear regression test for quantitative variables. Multivariable analysis based on stepwise selection at an alpha value of 0.05 was conducted to preserve the most relevant variables in the model and distinguish those independently associated with the outcomes. In all multivariable models, systematic adjustment for age was performed. Finally, we conducted diagnostic tests to ensure that the multivariable models satisfied linear regression model assumptions. All statistical analysis was carried out using R Studio version 4.0.2 (www.R-project.org).

Table 1 presents the characteristics of the participants by race. The groups differed in terms of age, BMI, KL radiographic grade, and pain catastrophizing. There were no significant differences between the groups in the levels of CRP, TNF-α, and IL-10, or in any WOMAC subscales. Each investigated inflammatory marker did not significantly correlate with BMI, which did not raise major concerns about multicollinearity (Table 2).

Table 2. Relationships between body mass index and inflammatory markers.

	Non-Hispanic Whites (n = 20)			Asian Americans (n = 20)
	log(CRP), ng/nl	log(TNF-α), pg/ml	log(IL-10), pg/ml	log(CRP), ng/nl	log(TNF-α), pg/ml	log(IL-10), pg/ml
Pearson correlation coefficient	0.179	-0.079	-0.190	0.364	0.292	0.218
p-value	.507	.740	.421	.115	.212	.356
18.5 ≤ BMI < 25^a	7.49 ± 1.53	2.22 ± 0.59	2.01 ± 0.71	6.13 ± 0.91	1.79 ± 0.62	1.74 ± 0.64
25 ≤ BMI < 30^b	6.75 ± 0.54	2.20 ± 0.33	1.97 ± 0.71	7.11 ± 0.79	1.97 ± 0.38	1.74 ± 0.33
BMI ≥ 30^c	7.73 ± 0.73	2.26 ± 0.64	1.87 ± 0.82	6.71 ± 1.07	2.22 ± 0.57	2.11 ± 0.67
ANOVA p-value	.194	.971	.929	.096	.551

Abbreviation. BMI, body mass index; CRP, C-reactive protein; IL-10, interleukin-10; TNF-α, tumor necrosis factor-alpha.

^aNon-Hispanic Whites (n = 5), Asian Americans (n = 11)

^bNon-Hispanic Whites (n = 9), Asian Americans (n = 7)

^cNon-Hispanic Whites (n = 6), Asian Americans (n = 2)

Table 3 presents the results of bivariate and multivariable analyses in both NHWs and Asian Americans. In NHWs, both analyses indicated that only pain catastrophizing was associated with worse WOMAC pain score and WOMAC functional score (p < .050). In Asian Americans, bivariate analysis indicated that CRP and TNF-α were associated with worse WOMAC pain score (r = 1.325, p = .041; r = 2.418, p = .036, respectively), while CRP was also related to worse WOMAC functional score (r = 4.950, p = .035). In multivariable analysis adjusting for age, only CRP was associated with worse WOMAC pain score (β = 1.328, p = .046) and WOMAC function score (β = 4.974, p = .034) in Asian Americans.

This pilot study investigated whether differences in the relationship between inflammation and knee OA symptoms (pain and physical function) exist between NHWs and Asian Americans. Our adjusted analyses concluded that CRP persists as a clinically relevant marker for both knee OA pain and functional disability in Asian Americans. The findings emphasize that inflammatory underpinnings of knee OA symptoms potentially vary among specific racial groups, echoing the results of Overstreet et al. (2024), which focused on patients with chronic low back pain.

However, the interpretation needs caution. The proportion of individuals with early-stage knee OA (KL radiographic grade: 0–1) significantly differed between the two groups, with 25% and 80% of NHWs and Asian Americans falling into this category, respectively. Evidence suggests that in early-stage knee OA, inflammation is a major reason why patients seek medical assistance in outpatient departments, and anti-inflammatory treatment may be more effective during this stage; in contrast, in late-stage knee OA, pain may not primarily originate from inflammation but rather from other sources that require further investigation (Li et al., 2020), a phenomenon corroborated by our study. Furthermore, in the current study, men constituted up 60.0% and 35.0% of the NHW and Asian American samples, respectively. Although this sex composition was not statistically significant, previous study has reported sex-specific relationships exhibiting weaker associations of CRP and TNF-α with knee pain among men (Perruccio et al., 2019); this possibly, in part, explains our insignificant findings for NHWs.

The finding wherein no relationships were established between inflammatory markers and knee OA symptoms among NHWs aligns with an earlier study predominantly based on NHW samples (Penninx et al., 2004). However, it contrasts with results reported by Zhu et al. (2016), who found serum CRP to be cross-sectionally and longitudinally associated with knee pain in patients with knee OA, as well as with other research reporting significant associations between knee OA pain and TNF-α (Loukov et al., 2018; Perruccio et al., 2019; Stannus et al., 2013). Nonetheless, direct comparisons are challenging owing to the unknown racial composition of these studies, our pilot study’s cross-sectional nature characterized by small sample sizes, varying socioeconomic and clinical characteristics across the study populations, and the multidimensional nature of pain assessed using various tools across the studies.

This pilot study has certain limitations. First, the findings may not be generalizable as they are based on an extremely small convenience sample from a specific region. Furthermore, owing to the small sample size, we could not account for or control heterogeneity within racial groups (ethnicity). Second, the presence of unknown or unmeasured confounding factors, such as the use of nonsteroidal anti-inflammatory drugs, comorbid conditions, psychosocial factors like depression or anxiety, and synovial inflammation, cannot be ruled out. Third, the cross-sectional design hindered our ability to determine the directionality of the relationships between variables. Finally, our study was limited by the number of biomarkers assayed.

Clinical Implications & Future Research Directions

As healthcare practices in the United States shift toward precision and targeted medicine, considering demographic factors that potentially influence mechanistic processes is imperative (Overstreet et al., 2024). We acknowledge that our pilot investigation may not have immediate clinical implications. However, our race-specific findings may inform healthcare providers that treatments chiefly developed based on NHW data may not provide optimal analgesic care for Asian Americans and suggest that the future development of novel OA treatment approaches may ultimately vary according to race, depending on the therapeutic target.

Based on our findings, future studies involving larger samples are required to validate our results and facilitate more advanced modeling (e.g., with mediators/moderators) to augment current knowledge. In addition, future studies may substantially benefit from leveraging a larger pool of biomarkers that could be analyzed as possible correlational factors for knee OA symptoms. Simultaneously, several studies, including our own, have relied on a single marker as a measure of inflammatory status; however, recognizing that the inflammatory system is complex and involves multiple feedback mechanisms is indispensable. For example, a study by Zhu et al. (2022) attempted to address these issues by examining the patterns of 19 different inflammatory markers and adipokines derived from principal component analysis and subsequently exploring their association with knee OA symptoms. Future studies should ascertain whether these associations differ across racial/ethnic groups and also include individuals from other racial/ethnic minority groups, such as non-Hispanic Blacks and Hispanics.

This pilot study provides pioneering evidence of race-specific relationships between inflammatory markers and knee OA symptoms among NHWs and Asian Americans. Based on our findings, racial/ethnic differences in this context warrant further exploration, with potential implications for the formulation of personalized strategies for managing knee OA symptoms.

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Tables 1 and 3 are available in the Supplementary Files section.

The authors declare no competing interests.

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Differential association of inflammation with pain and physical function in knee osteoarthritis by race: Focusing on non-Hispanic Whites and Asian Americans

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Version 1

Abstract

Introduction

Methods

Study Participants

Measurement

Knee OA Symptoms: Knee OA pain and physical function

Inflammatory Markers

Statistical Analysis

Results

Discussion

Clinical Implications & Future Research Directions

Conclusion

References

Tables

Additional Declarations

Supplementary Files

Status:

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