Novel immune biomarkers in complex regional pain syndrome

Russo, Marc; Georgius, Peter; Pires, Ananda Staats; Heng, Benjamin; Allwright, Michael; Guennewig, Boris; Santarelli, Danielle M.; Bailey, Dominic; Fiore, Nathan T.; Tan, Vanessa; Latini, Alexandra; Guillemin, Gilles J.; Austin, Paul J.

doi:10.1016/j.jneuroim.2020.577330

Cited by 17 publications

(26 citation statements)

References 77 publications

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“…49,50,53 Several clinical studies have also highlighted that the immune system and T-cells are critical components in the pathophysiology of CRPS patients. 54–57 This is consistent with the findings in a neuropathic animal model and CRPS patients. 79,80…”

Section: Discussionsupporting

confidence: 89%

Review of complex regional pain syndrome and the role of the neuroimmune axis

Prasad¹,

Chakravarthy

2021

Mol Pain

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Background Complex regional pain syndrome (CRPS) is a progressive and painful disease of the extremities that is characterized by continuous pain inconsistent with the initial trauma. CRPS is caused by a multi-mechanism process that involves both the peripheral and central nervous system, with a prominent role of inflammation in CRPS pathophysiology. This review examines what is currently known about the CRPS inflammatory and pain mechanisms, as well as the possible impact of neurostimulation therapies on the neuroimmune axis of CRPS. Study design A narrative review of preclinical and clinical studies provided an overview of the pain and inflammatory mechanisms in CRPS and addressed the effect of neurostimulation on immunomodulation. Methods A systematic literature search was conducted based on the PRISMA guidelines between September 2015 to September 2020. Data sources included relevant literature identified through searches of PubMed, Embase and the Cochrane Database of Systematic Reviews. Results Sixteen preclinical and eight clinical studies were reviewed. Preclinical studies identified different mechanisms of pain development in the acute and chronic CRPS phases. Several preclinical and clinical studies investigating inflammatory mechanisms, autoimmunity, and genetic profiles in CRPS, supported a role of neuroinflammation in the pathophysiology of CRPS. The immunomodulatory effects of neurostimulation therapy is still unclear, despite clinical improvement in the CRPS patients. Conclusions Increasing evidence supports a role for inflammation and neuroinflammation in CRPS pathophysiology. Preliminary neurostimulation findings, together with the role of (neuro)inflammation in CRPS, seems to provide a compelling rationale for its use in CRPS pain treatment. The possible immunomodulatory effects of neurostimulation opens new therapeutic possibilities, however further research is needed to gain a better understanding of the working mechanisms.

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Section: Discussionsupporting

confidence: 89%

Review of complex regional pain syndrome and the role of the neuroimmune axis

Prasad¹,

Chakravarthy

2021

Mol Pain

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Section: Crps Pathophysiologymentioning

confidence: 99%

“…Expanded populations of CD4+ and CD8+ lymphocytes in CRPS patients were documented in multiple studies, suggesting an antigen-mediated T lymphocyte response [ 29 , 30 ]. A recent study examining serum levels of pro- and anti-inflammatory cytokines in the serum of CRPS patients also identified IL-37 and GM-CSF as novel biomarkers in the immune response [ 29 ]. Decreased serum levels of IL-37 were found, indicating a suppression of the immune response through the activation of IL-10 and regulatory T lymphocytes [ 27 ].…”

Section: Crps Pathophysiologymentioning

confidence: 99%

“…Decreased serum levels of IL-37 were found, indicating a suppression of the immune response through the activation of IL-10 and regulatory T lymphocytes [ 27 ]. In contrast, an increase of GM-CSF was noted, highlighting a balance between pro- and anti-inflammatory cytokines in the pathogenesis of CRPS, with a predominantly pro-inflammatory state [ 27 , 29 ].…”

Section: Crps Pathophysiologymentioning

confidence: 99%

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Complex Regional Pain Syndrome: A Comprehensive Review

et al. 2021

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Complex regional pain syndrome (CRPS) is a chronic pain condition often involving hyperalgesia and allodynia of the extremities. CRPS is divided into CRPS-I and CRPS-II. Type I occurs when there is no confirmed nerve injury. Type II is when there is known associated nerve injury. Female gender is a risk factor for developing CRPS. Other risk factors include fibromyalgia and rheumatoid arthritis. Unfortunately, the pathogenesis of CRPS is not yet clarified. Some studies have demonstrated different potential pathways. Neuropathic inflammation, specifically activation of peripheral nociceptors of C-fibers, has been shown to play a critical role in developing CRPS. The autonomic nervous system (ANS) is involved. Depending on whether it is acute or chronic CRPS, norepinephrine levels are either

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“…A recent study has confirmed a role for GM-CSF in neuropathic pain, where it can potentiate the release of pro-inflammatory mediators from spinal glial cells (Nicol et al, 2018). Moreover, GM-CSF was identified as an important biomarker in our recent study in complex regional pain syndrome (Russo et al, 2020). The chemokine IL-8 is predominantly released from macrophages, recruits both neutrophils and T lymphocytes, and has recently been associated with neuropathic pain in burning mouth syndrome and peripheral neuropathies (Barry et al, 2018;Langjahr et al, 2018).…”

Section: Discussionmentioning

confidence: 53%

Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain

et al. 2020

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Neuropathic pain is a common complication of diabetes with high morbidity and poor treatment outcomes. Accumulating evidence suggests the immune system is involved in the development of diabetic neuropathy, whilst neuro-immune interactions involving the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways have been linked to neuropathic pain pre-clinically and in several chronic pain conditions. Here, using a multiplex assay, we quantified serum levels of 14 cytokines in 21 participants with type 1 diabetes mellitus, 13 of which were classified as having neuropathic pain. In addition, using high performance liquid chromatography and gas chromatography-mass spectrometry, all major KYN and BH4 pathway metabolites were quantified in serum from the same cohort. Our results show increases in GM-CSF and IL-8, suggesting immune cell involvement. We demonstrated increases in two inflammatory biomarkers: neopterin and the KYN/TRP ratio, a marker of indoleamine 2,3-dioxygenase activity. Moreover, the KYN/TRP ratio positively correlated with pain intensity. Total kynurenine aminotransferase activity was also higher in the diabetic neuropathic pain group, indicating there may be increased production of the KYN metabolite, xanthurenic acid. Overall, this study supports the idea that inflammatory activation of the KYN and BH4 pathways occurs due to elevated inflammatory cytokines, which might be involved in the pathogenesis of neuropathic pain in type 1 diabetes mellitus. Further studies should be carried out to investigate the role of KYN and BH4 pathways, which could strengthen the case for therapeutically targeting them in neuropathic pain conditions.

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Novel immune biomarkers in complex regional pain syndrome

Cited by 17 publications

References 77 publications

Review of complex regional pain syndrome and the role of the neuroimmune axis

Review of complex regional pain syndrome and the role of the neuroimmune axis

Complex Regional Pain Syndrome: A Comprehensive Review

Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain

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