Is fibromyalgia associated with a unique cytokine profile? A systematic review and meta-analysis

Abstract

Objectives: The aetiology of primary chronic pain syndromes (CPS) is highly disputed. We performed a systematic review and meta-analysis aiming to assess differences in circulating cytokine levels in patients with diffuse CPS (fibromyalgia) vs healthy controls (HC).

Methods: Human studies published in English from the PubMed, MEDLINE/Scopus and Cochrane databases were systematically searched from inception up to January 2020. We included full text cross-sectional or longitudinal studies with baseline cytokine measurements, reporting differences in circulating cytokine levels between fibromyalgia patients and HC. Random-effects meta-analysis models were used to report pooled effects and 95% CIs. This study is registered with PROSPERO (CRD42020193774).

Results: Our initial search yielded 324 papers and identified 29 studies (2458 participants) eligible for systematic review and 22 studies (1772 participants) suitable for meta-analysis. The systematic analysis revealed reproducible findings supporting different trends of cytokine levels when fibromyalgia patients were compared with HC, while the chemokine eotaxin, was consistently raised in fibromyalgia. Meta-analysis showed significantly increased TNF-α [standardized mean difference (SMD) = 0.36, 95% CI: 0.12, 0.60, P = 0.0034; I2 = 71%, Q2P = 0.0002], IL-6 (SMD = 0.15, 95% CI: 0.003, 0.29, P = 0.045; I2 = 39%, Q2P = 0.059), IL-8 (SMD = 0.26, 95% CI: 0.05, 0.47, P = 0.01; I2 = 61%, Q2P = 0.005) and IL-10 (SMD = 0.61, 95% CI: 0.34, 0.89, P < 0.001; I2 = 10%, Q2P = 0.34) in fibromyalgia patients compared with HC.

Conclusion: We found evidence of significant differences in the peripheral blood cytokine profiles of fibromyalgia patients compared with HC. However, the distinctive profile associated with fibromyalgia includes both pro-inflammatory (TNF-α, IL-6, IL-8) and anti-inflammatory (IL-10) cytokines in pooled analysis, as well as chemokine (eotaxin) signatures. Further research is required to elucidate the role of cytokines in fibromyalgia.

Keywords: chemokine; chronic pain syndromes; cytokines; eotaxin; fibromyalgia; meta-analysis; systematic review.

Fig. 1

Study selection algorithm CSF: cerebrospinal fluid.

Fig. 2

Meta-analysis for TNF-α Forest plots showing the pooled standardized mean difference of circulating TNF-α concentrations between fibromyalgia patients and controls. (A) All studies included; (B) outliers [Hernandez et al. (2010) and Togo et al. (2009)] excluded.

Fig. 3

Meta-analysis for IL-1 Forest plots showing the pooled standardized mean difference of circulating IL1 concentrations between fibromyalgia patients and controls. (A) All studies included; (B) studies reporting skewed (non-parametric) data excluded.

Fig. 4

Meta-analysis for IL-6 Forest plots showing the pooled standardized mean difference of circulating IL-6 concentrations between fibromyalgia patients and controls. (A) All studies included; (B) outliers [Hernandez et al. (2010)] excluded.

Fig. 5

Meta-analysis for IL-8 Forest plots showing the pooled standardized mean difference of circulating IL-8 concentrations between fibromyalgia patients and controls. (A) All studies included; (B) outliers [Mendieta et al. (2016)] excluded.

Fig. 6

Meta-analysis for IL-10 Forest plots showing the pooled standardized mean difference of circulating IL-10 concentrations between fibromyalgia patients and controls. (A) All studies included; (B) studies reporting skewed (non-parametric) data excluded.