Systemic Cytokine Level Differences in Patients with Chronic Musculoskeletal Spinal Pain Compared to Healthy Controls and Its Association with Pain Severity: A Systematic Review

CANLI, Kübra; Billens, Amber; Oosterwijck, Jessica Van; Meeus, Mira; Meulemeester, Kayleigh De

doi:10.1093/pm/pnac091

Cited by 15 publications

(8 citation statements)

References 48 publications

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“…It also extends upon prior studies reporting genetic correlations between CRP and back pain [11], osteoarthritis [21] & rheumatoid arthritis [21], by finding a genetic basis to higher CRP across a wider range of chronic pain phenotypes. Moreover, we have provided corroborating evidence for clinical studies showing higher CRP levels and other inflammatory markers in chronic back, neck & widespread pain [2][3][4]. Chronic musculoskeletal disorders (including spinal & widespread pain) are often co-morbid with many medical conditions that are also associated with higher CRP (e.g., obesity, cardiovascular disease) [22].…”

Section: Discussionsupporting

confidence: 75%

“…Accumulating evidence points to inflammatory mechanisms driving the development & maintenance of chronic spinal pain [1]. Systematic reviews report higher levels of blood inflammatory markers (e.g., C-reactive protein [CRP]) in back pain [2], neck pain [2,3] and fibromyalgia [4]. Higher CRP is associated with worse clinical outcomes in these patients, including increased pain, disability & hyperalgesia [5,6].…”

Section: Introductionmentioning

confidence: 99%

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Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain

et al. 2023

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Purpose Causal mechanisms underlying systemic inflammation in spinal & widespread pain remain an intractable experimental challenge. Here we examined whether: (i) associations between blood C-reactive protein (CRP) and chronic back, neck/shoulder & widespread pain can be explained by shared underlying genetic variants; and (ii) higher CRP levels causally contribute to these conditions. Methods Using genome-wide association studies (GWAS) of chronic back, neck/shoulder & widespread pain (N = 6063–79,089 cases; N = 239,125 controls) and GWAS summary statistics for blood CRP (Pan-UK Biobank N = 400,094 & PAGE consortium N = 28,520), we employed cross-trait bivariate linkage disequilibrium score regression to determine genetic correlations (rG) between these chronic pain phenotypes and CRP levels (FDR < 5%). Latent causal variable (LCV) and generalised summary data-based Mendelian randomisation (GSMR) analyses examined putative causal associations between chronic pain & CRP (FDR < 5%). Results Higher CRP levels were genetically correlated with chronic back, neck/shoulder & widespread pain (rG range 0.26–0.36; P ≤ 8.07E-9; 3/6 trait pairs). Although genetic causal proportions (GCP) did not explain this finding (GCP range − 0.32–0.08; P ≥ 0.02), GSMR demonstrated putative causal effects of higher CRP levels contributing to each pain type (beta range 0.027–0.166; P ≤ 9.82E-03; 3 trait pairs) as well as neck/shoulder pain effects on CRP levels (beta [S.E.] 0.030 [0.021]; P = 6.97E-04). Conclusion This genetic evidence for higher CRP levels in chronic spinal (back, neck/shoulder) & widespread pain warrants further large-scale multimodal & prospective longitudinal studies to accelerate the identification of novel translational targets and more effective therapeutic strategies.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain

et al. 2023

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“… 2 High levels of IL-1, IL-1β, IL-6, IL-17, and TNF-α were thought to accelerate the occurrence and progression of LBP. 5 , 55 , 56 In addition, other pro-inflammatory cytokines (eg, IL-12 and IL-23) have also been shown to be associated with the presence of LBP. 4 , 57 …”

Section: Discussionmentioning

confidence: 99%

Effect of Moxibustion on Inflammatory Cytokines for Low Back Pain: A Systematic Review, Meta-Analysis and Meta-Regression

Zhao,

Li,

Wen

et al. 2023

TCRM

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Background and Objective Moxibustion is effective for low back pain (LBP), and inflammatory cytokines may play an important role in the mechanism of moxibustion treatment. The purpose of this meta-analysis was to explore the mechanism of moxibustion in LBP in terms of inflammatory cytokines. Methods We searched China National Knowledge Infrastructure, Wanfang database, Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Embase, PubMed, and Web of Science to identify eligible randomized controlled trials (RCTs). There was no restriction on the publication date. Results Thirty RCTs measuring interleukin (IL-) 1, IL-1β, IL-6, IL-12, IL-17, IL-23, and tumor necrosis factor (TNF-) α were included in this meta-analysis. Compared to controls: single moxibustion could effectively decrease levels IL-6 and IL-23 (SMD, −0.71, 95% CI: −1.25 to −0.17, p = 0.01; SMD, −1.61, 95% CI: −2.20 to −1.03, p < 0.01, respectively); combined moxibustion had significant effects on IL-1, IL-1β, IL-6, IL-12, IL-17, and TNF-α ( p < 0.05). Overall, for LBP, single or combined moxibustion could effectively down-regulate levels of pro-inflammatory cytokines ( p = 0.007 and p < 0.00001, respectively). For safety of moxibustion, the incidence rate of side effects was similar to that of controls (RD, −0.01, 95% CI: −0.02 to 0.01, p = 0.59). Sensitivity analysis showed that the pooled estimates were robust, and publication bias analysis showed there was a significant small study effect (Egger’s test p = 0.0000). High statistical heterogeneity existed between included RCTs, meta-regression showed there was no potential factor explaining the source of heterogeneity. Conclusion For LBP, moxibustion can effectively decrease levels of IL-1, IL-1β, IL-6, IL-12, IL-17, IL-23, and TNF-α to achieve analgesia. Because the side effects of moxibustion are transient, it is relatively safe for clinical use. However, based on high heterogeneity in this meta-analysis, rigorously designed RCTs are required to further confirm the results in this review.

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“…Increased inflammation has been shown repeatedly in several pain populations, e.g., [36][37][38][39][40][41] in the past decade, and many inflammatory mechanisms involved in the chronification of pain have emerged [6,7,11,41,43]. For rheumatoid arthritis, immunological treatments are useful for many patients [35].…”

Section: Inflammation and Painmentioning

confidence: 99%

How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review

Benson,

Karshikoff

2023

Neuroimmunomodulation

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Background: The immune system and the central nervous system exchange information continuously. This communication is a prerequisite for adaptive responses to physiological and psychological stressors. While the implicate relationship between inflammation and pain is increasingly recognized in clinical cohorts, the underlying mechanisms and the possibilities for pharmacological and psychological approaches aimed at neuro-immune communication in pain are not fully understood yet. This calls for preclinical models which build a bridge from clinical research to laboratory research. Summary: Experimental models of systemic inflammation (experimental endotoxemia) in humans have been increasingly recognized as an approach to study the direct and causal effects of inflammation on pain perception. This narrative review provides an overview of what experimental endotoxemia studies on pain have been able to clarify so far. We report that experimental endotoxemia results in a reproducible increase in pain sensitivity, particularly for pressure and visceral pain (deep pain), which is reflected in responses of brain areas involved in pain processing. Increased levels of blood inflammatory cytokines are required for this effect, but cytokine levels do not always predict pain intensity. We address sex-dependent differences in immunological responses to endotoxin, and discuss why these differences do not necessarily translate to differences in behavioral measures. We summarize psychological and cognitive factors that may moderate pain sensitization driven by immune activation. Key messages: Together, studying the immune-driven changes in pain during endotoxemia offers a deeper mechanistic understanding of the role of inflammation in chronic pain. Experimental endotoxemia models can specifically help to tease out inflammatory mechanisms underlying individual differences, vulnerabilities, and comorbid psychological problems in pain syndromes. The model offers the opportunity to test the efficacy of interventions, increasing their translational applicability for personalized medical approaches.

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Systemic Cytokine Level Differences in Patients with Chronic Musculoskeletal Spinal Pain Compared to Healthy Controls and Its Association with Pain Severity: A Systematic Review

Cited by 15 publications

References 48 publications

Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain

Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain

Effect of Moxibustion on Inflammatory Cytokines for Low Back Pain: A Systematic Review, Meta-Analysis and Meta-Regression

How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review

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