Background & Aims

Fibromyalgia is a common chronic pain condition that is characterized by chronic widespread pain and hypersensitivity.(1) The cause is poorly understood but seems multifactorial, with different central and peripheral mechanisms as possible reinforcements of altered pain processing.(2)
One possible pathophysiologic mechanism is central neuroinflammation causing hypersensitivity in central pain processing, but the search for possible neuroimmune biomarkers related to the pain symptoms has so far been inconclusive. (3-6)
The cause is poorly uncertain but several studies have indicated that a central neuro-inflammatory process may be part of the pathophysiology but this still needs to be confirmed in larger human studies.
The aim of this study was to examine differences in neuroimmune biomarkers in the cerebrospinal fluid of participants with fibromyalgia and painfree volunteers and whether these biomarkers were associated to clinical outcomes.

Methods

CSF from 115 participants with Fibromyalgia and 70 pain free volunteers , included in the DANPAIN-biobank were examined.
Concentrations of TNF, IL-8, IL-6, IL-1?, IL-1?, and IL-1Ra , were measured using V-PLEX Custom Human Proinflammatory Panel1 Biomarker assay, while TNFRI, TNFRII and IL-6R were
measured using a R-PLEX Human assay/TNF-RII assay from Mesoscale. We used multiple regression with robust standard errors to compare the concentrations of the biomarkers between the two groups while accounting for the possible confounders: age, sex, bmi, plate distribution.
Clinical outcomes were NRS-score and FIQR-score. The association to clinical outcomes were explored using multiple regression with stepwise backward selection of the biomarkers as independent variables. Predictors with p<0.1 was included to achieve the best predictive model.

Results

TNFR1 was significantly reduced in patients with fibromyalgia (coefficient=-125.9, 95% CI=-245.5;-6.3; p=0.039) while there were no significant differences between the two groups for the remaining biomarkers. For several biomarkers, the 95% CI however indicated possible significans: TNFR2 (coefficient=-113.4 , 95% CI=-232.3;5.4; p=0.061), IL-1? (coefficient=-0.3, 95% CI=-0.6;0.01; p=0.061), IL-1? (coefficient=-0.3 , 95% CI=(-0.6;0.01; p=0.059), IL-1RA (coefficient=-3.3 , 95% CI=(-6.8;0.1; p=0.059).

NRS-score was predicted by the combination of elevated concentrations of TNF and IL-6R and reduced levels of TNFR1 and IL-6 (R2=0.1, p=0.0007).
FIQR-score was predicted by the combination of elevated concentrations of TNF, IL-1? and IL-1RA and reduced levels of IL-6 (R2=0.12, p=0.0004).

Conclusions

Only TNFR1 differed significantly between the two groups but the combination of several biomarkers from several different cytokine families was significantly associated to clinical outcomes.
The neuroimmune system has a high level of complexity with multiple complex and subtle cascade and feedback mechanisms. Thus, a multivariate approach to assess the interaction of neuroimmune biomarkers and their role in pathophysiological processes may be relevant to advance the understanding of the role of neuroimmune processes i fibromyalgia and chronic pain.

References

1. Heidari F, Afshari M, Moosazadeh M. Prevalence of fibromyalgia in general population and patients, a systematic review and metaanalysis. Rheumatol Int 2017; 37: 1527–39.
2. Pinto AM, Luís M, Geenen R, et al. Neurophysiological and psychosocial mechanisms of fibromyalgia: a comprehensive review and call for an integrative model. Neurosci Biobehav Rev 2023;
151: 105235.
3. Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. Anesthesiology. 2018;129:343-366.
4. Cagnie B, Coppieters I, Denecker S, Six J, Danneels L, Meeus M. Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Semin Arthritis Rheum 2014;44: 68–75.
5. Vergne-Salle P, Bertin P. Chronic pain and neuroinflammation. Joint Bone Spine. 2021;88: Article 105222.
6. Bäckryd E, Tanum L, Lind AL, et al. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res 2017;10:515-25.

Presenting Author

Morten Blichfeldt-Eckhardt

Poster Authors

Morten Blichfeldt-Eckhardt

MD, PH.D

University Hospital of Southern Denmark

Lead Author

Kate Lykke Lambertsen

University of Southern Denmark

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Fibromyalgia