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Signs of ongoing inflammation in female patients with chronic widespread pain: A multivariate, explorative, cross-sectional study of blood samples.

ABSTRACT: This cross-sectional study investigates the plasma inflammatory profile of chronic widespread pain (CWP) patients compared to healthy controls (CON). Rather than analyzing a relatively few substances at a time, we used a new multiplex proximity extension assay (PEA) panel that enabled the simultaneous analysis of 92 inflammation-related proteins, mainly cytokines and chemokines.Seventeen women with CWP and 21 female CON participated and a venous blood sample was drawn from all subjects. Pain intensity and pain thresholds for pressure, heat, and cold were registered. A PEA panel (92 proteins) was used to analyze the blood samples. Multivariate data analysis by projection was used in the statistical analyses.Eleven proteins significantly differentiated the CON and CWP subjects (R?=?0.58, Q?=?0.37, analysis of variance of cross-validated predictive residuals P?=?0.006). It was not possible to significantly regress pain thresholds within each group (CON or CWP). Positive significant correlations existed between several proteins and pain intensities in CWP, but the model reliability of the regression was poor.CWP was associated with systemic low-grade inflammation. Larger studies are needed to confirm the results and to investigate which alterations are condition-specific and which are common across chronic pain conditions. The presence of inflammation could promote the spreading of pain, a hallmark sign of CWP. As it has been suggested that prevalent comorbidities to pain (e.g., depression and anxiety, poor sleep, and tiredness) also are associated with inflammation, it will be important to determine whether inflammation may be a common mediator.

SUBMITTER: Gerdle B

PROVIDER: S-EPMC5340439 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Signs of ongoing inflammation in female patients with chronic widespread pain: A multivariate, explorative, cross-sectional study of blood samples.

Gerdle Björn B Ghafouri Bijar B Ghafouri Nazdar N Bäckryd Emmanuel E Gordh Torsten T

Medicine 20170301 9

This cross-sectional study investigates the plasma inflammatory profile of chronic widespread pain (CWP) patients compared to healthy controls (CON). Rather than analyzing a relatively few substances at a time, we used a new multiplex proximity extension assay (PEA) panel that enabled the simultaneous analysis of 92 inflammation-related proteins, mainly cytokines and chemokines.Seventeen women with CWP and 21 female CON participated and a venous blood sample was drawn from all subjects. Pain int ...[more]

PMID: 28248866

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Project description:INTRODUCTION:Frequent chronic local pain can develop into chronic widespread pain (CWP). The spread of pain is correlated with pain intensity, anxiety, and depression, conditions that ultimately lead to a poor quality of life. Knowledge is incomplete about CWP's etiology, although it has been suggested that both central hyperexcitability and/or a combination with peripheral factors may be involved. Cerebrospinal fluid (CSF) could act as a mirror for the central nervous system as proteins are signal substances that activate the formation of algesics and control nociceptive processes. To this end, this study investigates the CSF protein expression in women with CWP and in female healthy controls. MATERIALS AND METHODS:This study included 12 female patients with CWP diagnosed according to the American College of Rheumatology criteria with 13 healthy age- and sex-matched pain-free subjects. All subjects went through a clinical examination and answered a health questionnaire that registered sociodemographic and anthropometric data, pain characteristics, psychological status, and quality of life rating. CSF was collected by lumbar puncture from each subject. Two-dimensional gel electrophoresis in combination with mass spectrometry was used to analyze the CSF proteome. This study identifies proteins that significantly discriminate between the two groups using multivariate data analysis (MVDA) (i.e., orthogonal partial least squares discriminant analysis [OPLS-DA]). RESULTS:There were no clinically significant levels of psychological distress and catastrophization presented in subjects with CWP. MVDA revealed a highly significant OPLS-DA model where 48 proteins from CSF explained 91% (R2) of the variation and with a prediction of 90% (Q2). The highest discriminating proteins were metabolic, transport, stress, and inflammatory. CONCLUSION:The highest discriminating proteins (11 proteins), according to the literature, are involved in apoptotic regulations, anti-inflammatory and anti-oxidative processes, the immune system, and endogenous repair. The results of this explorative study may indicate the presence of neuro-inflammation in the central nervous system of CWP patients. Future studies should be larger and control for confounders and determine which alterations are unspecific/general and which are specific changes.

Project description:BackgroundDifferent functional somatic syndromes (FSS), fibromyalgia (FMS) and other unexplained painful conditions share many common clinical traits and are characterized by troubling and functionally disabling somatic symptoms. Chronic pain is most frequently reported and at the center of patients' level of disease burden. The construct of multisomatoform disorder (MSD) allows to subsume severely impaired patients suffering from FSS, FMS and other unexplained painful conditions to be examined for common underlying processes. Altered leptin levels and a pathological response of the HPA-axis as a result of chronic stress and childhood trauma have been suggested as one of the driving factors of disease development and severity. Previous studies have demonstrated that methylation of the leptin promoter can play a regulatory role in addiction. In this study, we hypothesized that methylation of the leptin promoter is influenced by the degree of childhood traumatization and differs between patients with MSD and controls. A cohort of 151 patients with MSD and 149 matched healthy volunteers were evaluated using clinical and psychometric assessment while methylation level analysis of the leptin promoter was performed using DNA isolated from whole blood.ResultsIn female controls, we found CpG C-167 to be negatively correlated with leptin levels, whereas in female patients CpG C-289, C-255, C-193, C-167 and methylation cluster (C-291 to C-167) at putative bindings sites for transcription factors Sp1 and c/EBPalpha were negatively correlated with leptin levels. Methylation levels were significantly lower in female patients CpG C-289 compared with controls. When looking at female patients with chronic widespread pain methylation levels were significantly lower at CpG C-289, C-255 and methylation cluster (C-291 to C-167).ConclusionOur findings support the hypothesis that epigenetic regulation of leptin plays a role in the regulation of leptin levels in patients with MSD. This effect is more pronounced in patients with chronic widespread pain.

Project description:Chronic widespread pain (CWP), including fibromyalgia (FM), is characterized by generalized musculoskeletal pain. An important clinical feature is widespread increased pain sensitivity such as lowered pain thresholds for different stimuli such as heat (HPT) and cold (CPT). There is a growing interest in investigating the activated neurobiological mechanisms in CWP. This explorative proteomic study investigates the multivariate correlation pattern between plasma and muscle proteins and thermal pain thresholds in CWP and in healthy controls (CON). In addition, we analysed whether the important proteins and their networks for CPT and HPT differed between CWP and CON. We used a proteomic approach and analysed plasma and muscle proteins from women with CWP (n = 15) and CON (n = 23). The associations between the proteins and CPT/HPT were analysed using orthogonal partial least square (OPLS). The protein-protein association networks for the important proteins for the two thermal pain thresholds were analysed using STRING database. CWP had lowered pain thresholds for thermal stimulus. These levels were generally not related to the included clinical variables except in CWP for HPT. Highly interacting proteins mainly from plasma showed strong significant associations with CPT and HPT both in CWP and in CON. Marked differences in the important proteins for the two thermal pain thresholds were noted between CWP and CON; more complex patterns emerged in CWP. The important proteins were part of the immune system (acute phase proteins, complement factors, and immunoglobulin factors) or known to interact with the immune system. As expected, CWP had lowered pain thresholds for thermal stimulus. Although different proteins were important in the two groups, there were similarities. For example, proteins related to the host defence/immunity such as acute phase proteins, complement factors, immunoglobulin factors, and cytokines/chemokines (although not in CON for CPT) were important habitual/tonic factors for thermal pain thresholds. The fact that peripheral proteins contribute to thermal pain thresholds does not exclude that central factors also contribute and that complex interactions between peripheral and central factors determine the registered pain thresholds in CWP.

Project description:BackgroundThis study compares the levels of algesic substances between subjects with trapezius myalgia (TM) and healthy controls (CON) and explores the multivariate correlation pattern between these substances, pain, and metabolic status together with relative blood flow changes reported in our previous paper (Eur J Appl Physiol 108:657-669, 2010).Methods43 female workers with (TM) and 19 females without (CON) trapezius myalgia were - using microdialysis - compared for differences in interstitial concentrations of interleukin-6 (IL-6), bradykinin (BKN), serotonin (5-HT), lactate dehydrogenas (LDH), substance P, and N-terminal propeptide of procollagen type I (PINP) in the trapezius muscle at rest and during repetitive/stressful work. These data were also used in multivariate analyses together with previously presented data (Eur J Appl Physiol 108:657-669, 2010): trapezius muscle blood flow, metabolite accumulation, oxygenation, and pain development and sensitivity.ResultsSubstance P was significantly elevated in TM (p=0.0068). No significant differences were found in the classical algesic substances (p: 0.432-0.926). The multivariate analysis showed that blood flow related variables, interstitial concentrations of metabolic (pyruvate), and algesic (BKN and K+) substances were important for the discrimination of the subjects to one of the two groups (R2: 0.19-0.31, p<0.05). Pain intensity was positively associated with levels of 5-HT and K+ and negatively associated with oxygenation indicators and IL-6 in TM (R2: 0.24, p<0.05). A negative correlation existed in TM between mechanical pain sensitivity of trapezius and BKN and IL-6 (R2: 0.26-0.39, p<0.05).ConclusionThe present study increased understanding alterations in the myalgic muscle. When considering the system-wide aspects, increased concentrations of lactate, pyruvate and K+ and decreased oxygenation characterized TM compared to CON. There are three major possible explanations for this finding: the workers with pain had relatively low severity of myalgia, metabolic alterations preceded detectable alterations in levels of algesics, or peripheral sensitization and other muscle alterations existed in TM. Only SP of the investigated algesic substances was elevated in TM. Several of the algesics were of importance for the levels of pain intensity and mechanical pain sensitivity in TM. These results indicate peripheral contribution to maintenance of central nociceptive and pain mechanisms and may be important to consider when designing treatments.

Dataset Information

Signs of ongoing inflammation in female patients with chronic widespread pain: A multivariate, explorative, cross-sectional study of blood samples.

Publications

Signs of ongoing inflammation in female patients with chronic widespread pain: A multivariate, explorative, cross-sectional study of blood samples.

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