Short communicationEvaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with fibromyalgia – A controlled cross-sectional study
Introduction
Fibromyalgia (FM) is a common disease with a complex and not completely known pathophysiology. Along with generalized pain, depression is frequently present in the disease context, which a prevalence ranging from 28.6% to 70% [1].
There are no reliable laboratory markers of disease activity or severity in FM. Studies evaluating levels of interleukins (IL), including IL-6, IL-8, IL-10, IL-4, and IL-2, as well as tumor necrosis factor (TNF-α) in FM, have rendered inconsistent results [2], [3], [4], [5], [6]. Higher levels of brain-derived neurotrophic factor (BDNF) was found in blood and cerebrospinal fluid (CSF) of FM patients [7], [8], [9]. There is also evidence of increased levels of biomarkers of oxidative stress (like protein carbonyl content and Thiobarbituric Acid Reactive Substances (TBARS) in FM [10], [11]. However, it is possible that the interplay between biomarkers is more important than their isolated levels in certain diseases. In view of that, Kapczinski and colleagues developed a multi-biomarker score for mood disorders called Systemic Toxicity Index (STI), which differentiated patients with mania or depression from healthy control subjects [12]. The STI has not been studied in patients with FM so far.
Our aim in this study is to investigate the serum concentrations of cytokines (IL-6, IL-8, IL-10 and TNF-α), BDNF and stress oxidative biomarkers (carbonyl and TBARS), as wells as their interconnection using the STI, in patients with FM in comparison to healthy controls. We also test the possibility of association of the biomarkers with the severity of FM and depression in these patients.
Section snippets
Study design and participants
A prospective controlled cross-sectional study was conducted at the Rheumatology Departments of the Hospital das Clínicas da Universidade Federal de Pernambuco (HC/UFPE) and Hospital de Clínicas de Porto Alegre (HCPA). Subjects’ recruitment and data collection occurred between Sep/2011 and Nov/2012.
The patients were consecutively selected from the outpatient clinic specialized in the care of fibromyalgia patients at the HC/UFPE. All subjects fulfilled both the American College of Rheumatology
Results
We recruited 69 FM patients and 61 controls (all female). Age was similar between groups (44.5 ± 6.4 years in FM and 44.0 ± 6.7 in controls). The clinical data of FM patients are described in Table 1. The FM patient had in general long disease duration, almost half were using antidepressant drugs (in doses for treatment of depression) and the overall impact of FM on quality of life, measured by FIQ, was high (70.2 ± 17.8). Most FM patients had at least some level of depression (82.5% by BDI and 87.0%
Discussion
Fibromyalgia is a complex and heterogeneous condition characterized by a disorder in pain processing associated with other defined secondary symptoms and poor quality of life [16]. The prevalence of mood disturbance in FM is about three times higher than in the general population [1]. Mood disturbance has been related to altered levels of some biomarkers. Two meta-analysis showed significantly higher levels of IL-6 and TNF-α in patients with major depression [17], [18]. Substances linked to an
Conclusion
Our results do not support that the levels of cytokines (except perhaps for IL-10), markers of oxidative stress and BDNF are higher in FM patients, and we did not find correlations between depression and the biomarkers in these patients. Additional studies and better standardization of research methods is still needed in this field.
Funding
This work was supported in part by grants from Fundo de Incentivo à Pesquisa e Eventos (FIPE) of Hospital de Clínicas de Porto Alegre (HCPA). The funder was not involved in writing, study design, collection, analysis or interpretation of data.
Conflict of interest statement
The authors declare no conflicts of interest.
References (34)
- et al.
Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels
J. Neuroimmunol.
(2012) - et al.
Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants
J. Psychiatr. Res.
(2007) - et al.
Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome
J. Pain: Official J. Am. Pain Soc.
(2007) - et al.
Peripheral biomarkers and illness activity in bipolar disorder
J. Psychiatr. Res.
(2011) - et al.
A meta-analysis of cytokines in major depression
Biol. Psychiatry
(2010) - et al.
A review of peripheral biomarkers in major depression: the potential of inflammatory and oxidative stress biomarkers
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2014) - et al.
IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients
J. Neuroimmunol.
(2016) - et al.
Psychiatric problems in fibromyalgia: clinical and neurobiological links between mood disorders and fibromyalgia
Reumatismo
(2012) - et al.
Attachment style and cytokine levels in patients with fibromyalgia: a prospective longitudinal study
Schmerz
(2014) - et al.
Inflammatory/stress feedback dysregulation in women with fibromyalgia
Neuroimmunomodulation
(2012)
MCP-1 and IL-8 as pain biomarkers in fibromyalgia: a pilot study
Pain Med.
Circulating cytokine levels compared to pain in patients with fibromyalgia – a prospective longitudinal study over 6 months
J. Rheumatol.
Increased plasma levels of brain derived neurotrophic factor (BDNF) in patients with fibromyalgia
Neurochem. Res.
Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns
Rheumatol. Int.
Levels of lipid peroxidation, nitric oxide, and antioxidant vitamins in plasma of patients with fibromyalgia
Cell Biochem. Funct.
Validation of the Brazilian version of the Fibromyalgia Impact Questionnaire (FIQ)
Rev. Bras. Reumatol.
Validation of a Portuguese version of the beck depression inventory and the state-trait anxiety inventory in Brazilian subjects
Braz. J. Med. Biol. Res.
Cited by (42)
Cannabinoids and the endocannabinoid system in fibromyalgia: A review of preclinical and clinical research
2022, Pharmacology and TherapeuticsCitation Excerpt :Abnormalities have been detected in cerebrospinal fluid of patients with FM, including elevated levels of substance P (Russell, Littman, & Alboukrek, 1994), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) (Sarchielli, Floridi, Rossi, Acciarresi, & Calabresi, 2007) and lower levels of serotonin metabolites (Russell, 1992). Conflicting reports of normative and elevated levels of BDNF and NGF have also been reported in serum and plasma samples of patients with FM (Nugraha & Gutenbrunner, 2013; Ranzolin, 2016). Serum levels of BDNF have been found to be age-dependent in healthy controls which could account for the conflicting reports if appropriate age-matched controls were not used (Nugraha & Gutenbrunner, 2013).
Serum interleukin-6 in primary fibromyalgia syndrome patients: Impact on disease burden, severity, quality of life and sleep
2022, Egyptian RheumatologistCitation Excerpt :Increased level of substance P in its turn induces the release of IL-6 [30]. On the contrary to the previous results, Ranzolin et al. found no difference in the biomarker levels between FMS patients and control [31]. There was a significant correlation between IL and 6 levels and clinical scores of fatigue severity, sleep quality, pain severity and quality of life but not with the disease duration in FMS patients.
Characterization of β-cyclodextrin/myrtenol complex and its protective effect against nociceptive behavior and cognitive impairment in a chronic musculoskeletal pain model
2020, Carbohydrate PolymersCitation Excerpt :Fibromyalgia is common in the general population, especially women, with prevalence rates of 7.3%–12.9% across different countries (Cabo-Meseguer, Cerdá-Olmedo, & Trillo-Mata, 2017; Heidari, Afshari, & Moosazadeh, 2017). Patients with fibromyalgia are exposed to oxidative stress, and despite it being a non-inflammatory rheumatic syndrome, cytokines such as IL-6, IL-8 (Wallace, Gavin, Karpenko, Barkhordar, & Gillis, 2015) and IL-10 have been found to be altered in fibromyalgia (Ranzolin et al., 2016). The syndrome involves multiple symptoms and comorbidities, with no single ideal treatment, and thus requires both pharmacological and non-pharmacological approaches, based on the control of the specific symptoms, particularly pain (Sumpton & Moulin, 2014).
Immune-inflammatory pathways and clinical changes in fibromyalgia patients treated with Mindfulness-Based Stress Reduction (MBSR): A randomized, controlled clinical trial
2019, Brain, Behavior, and ImmunityCitation Excerpt :There are some cytokines that are associated with FM, including higher levels of IL-6, TNF-α and CXCL8, and lower levels of IL-4 and IL-10 (Rodriguez-Pinto et al., 2014; Üçeyler et al., 2011). Although there is not a clear consensus (Ranzolin et al., 2016), research suggests that unbalanced levels of pro-inflammatory versus anti-inflammatory cytokines in FM may lead to a chronic mild inflammatory state in central and peripheral nervous systems, lowering the pain threshold and facilitating the sensitization of peripheral nerves to nociceptive stimuli (Rodriguez-Pinto et al., 2014). In this regard, several studies have reported higher levels of pro-inflammatory cytokines or chemokines (i.e. IL-1, IL-6, CXCL8, and TNF-α) and lower levels of anti-inflammatory cytokines (i.e. IL-4, IL-5, IL-10, and IL-13) in FM (Littlejohn, 2015; Rodriguez-Pinto et al., 2014; Sturgill et al., 2013; Üçeyler et al., 2011; Bäckryd et al., 2017), coupled with higher levels of hs-CRP (Feinberg et al., 2017).
Physiopathology of fibromyalgia
2020, Reumatologia Clinica