The association between inflammatory biomarkers and low back disorder: a systematic review and meta-analysis.

INTRODUCTION: Low back disorder (LBD) is a major cause of disability worldwide. Inflammation results in proliferation of cytokines or consequent degradation products (collectively known as inflammatory biomarkers) that activate pain pathways which can result in non-specific LBD. This systematic review and meta-analysis aim to evaluate the relationship between inflammatory biomarkers and clinical outcomes in patients with LBD. METHODS: The PRISMA guideline was followed for the systematic reivew. Three online databases were searched. Four RCTs and sixteen observational studies with 1142 LBD patients were analysed. The primary outcomes were back and leg pain scores, back-specific disability scores and expression of inflammatory biomarkers. Standardized mean difference (SMD) and their 95% confidence intervals (CI) were evaluated. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to summarize the strength of evidence. RESULTS: Four RCTs and sixteen observational studies were included in the analysis of 1142 patients with LBD. There was a statistically significant reduction in back pain score and IL-1 beta and increase in the expression of CTX-1 and IL-10 levels post treatment. There was a significant relationship between increase in the expression of MCP- and reduction in the expression of hsCRP with increase in back pain. Significant relationship was also observed between increase in the expression of MCP-1 and reduction in the expression of IL-6 with increase in leg pain. Increase in the expression of IL-8 and reduction in the expression of hsCRP was also associated with increased disability score. CONCLUSION: Inflammatory biomarkers play a significant role in the pathogenesis of LBD. CTX-1, IL-10 and IL-1 beta may be responsible for the decrease in back pain scores post treatment. There is a relationship between MCP-1, IL-6, IL-8 and hsCRP with clinical and functional assessments for LBD. Further studies will improve understanding of the pathogenesis of LBD and aid in targeted management strategies.

The association of biomarkers with pain and function in acute and subacute low back pain: a secondary analysis of an RCT.

BACKGROUND: Low back pain (LBP) is a common musculoskeletal condition and a major cause of disability worldwide. Previous studies have found associations of biomarkers with pain and pain-related disability in LBP patients. This study aimed to explore the association between serum biomarkers and pain and disability in patients with acute or subacute axial LBP. METHODS: This study was ancillary to a parent randomized controlled trial. Enrolled participants were randomized into three intervention groups: one of two types of spinal manipulation or medical care. In the parent study, 107 adults who experienced a new episode of LBP within 3 months prior to enrollment were recruited. For this study, 90 of these 107 participants consented to have blood samples obtained, which were drawn immediately before the beginning of treatment. Seven biomarkers were chosen based on previous literature and analyzed. Clinical outcomes were pain and Oswestry Disability Index (ODI) evaluated at baseline and 4 weeks. Spearman's |r| was used to study the association of initial levels of each biomarker with pain and ODI scores at baseline and with changes in outcome scores from baseline to 4 weeks (end of treatment) within each intervention group. RESULTS: At baseline, 4 of 7 biomarkers had an association with pain that was |r| ≥ .20: neuropeptide Y (NPY) (r = 0.23, p = .028), E-Selectin (r = 0.22, p = .043), vitamin D ((r = - 0.32, p = .002), and c-reactive protein (CRP) (r = 0.37, p = .001). No baseline biomarker had an association with disability that was |r| ≥ 0.20. For the correlations of baseline biomarkers with 4-week change in outcomes, vitamin D showed a correlation with change in disability and/or pain (|r| ≥ 0.20, p > .05) in manipulation-related groups, while CRP, NPY, and E-selectin along with TNFα, Substance P and RANTES showed at least one correlation with change in pain or disability (|r| ≥ 0.20, p > .05) in at least one of the treatment groups. CONCLUSIONS: In 90 LBP patients, the analyzed biomarkers, especially vitamin D, represent a small set of potential candidates for further research aimed at individualizing patient care. Overall, the associations investigated in the current study are an initial step in identifying the direct mechanisms of LBP and predicting outcomes of manipulation-related treatments or medical care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01211613, Date of Registration: September 29, 2010, https://clinicaltrials.gov/ct2/show/NCT01211613?term=schneider&cond=Low+Back+Pain&cntry=US&state=US%3APA&draw=2&rank=1.

Severity of intervertebral disc herniation regulates cytokine and chemokine levels in patients with chronic radicular back pain.

OBJECTIVE: The contributions of intervertebral disc disease and subject-specific covariates to systemic inflammation in low back pain are unknown. We examined the effects of symptomatic disc herniation (DH) and MRI herniation severity on serum cytokine levels in clinical subjects. DESIGN: Cytokine levels from lumbar DH subjects (N = 78) were compared to control subjects (N = 57) accounting for effects of DH, age, body mass index (BMI) and gender. Effect of DH severity on cytokine levels was analyzed on subsets of subjects with acute or chronic pain. Serum cytokines were also analyzed in a subset of patients between pre- and 3 months post-surgery. RESULTS: Cytokine levels were elevated in the serum of patients with symptomatic DH, and the covariates age, BMI and gender significantly contributed to levels of some cytokines. Severity of herniation was a significant contributor to pain intensity (VAS), serum levels of HMGB1, PDGFbb, and IL-9. The relationship between DH severity and cytokine levels was confirmed in subjects with chronic, but not acute symptoms. Serum levels of macrophage migration inhibitory factor (MIF) decreased, whereas levels of CCL3, CCL11, CXCL1, and CXCL10 were significantly elevated post surgery. CONCLUSIONS: This study is the first to show that DH severity is coordinately associated with changes in serum levels of inflammatory cytokines in chronic pain subjects. HMGB1, PDGFbb and IL-9 are novel mediators of increasing DH severity, indicative of cellular damage, neuro-inflammation and angiogenesis. Resolution of inflammation was observed with decrease in MIF post surgery. However, elevated chemokine levels indicate ongoing remodeling and wound healing at 3-month time point.

A systematic review of the role of inflammatory biomarkers in acute, subacute and chronic non-specific low back pain.

BACKGROUND: Low back pain (LBP) is one of the greatest contributors to disability in the world and there is growing interest on the role of biomarkers in LBP. To purpose of this review was to analyze available evidence on the relationship between inflammatory biomarkers, clinical presentation, and outcomes in patients with acute, subacute and chronic non-specific low back pain (NSLBP). METHODS: A search was performed in Medline, Embase, Cinahl and Amed databases. Studies which measured levels of inflammatory biomarkers in participants with NSLBP were included. Two reviewers independently screened titles and abstracts, full-texts, and extracted data from included studies. Methodological quality was assessed using the Newcastle Ottawa Quality Assessment Scale. Level of evidence was assessed using the modified GRADE approach for prognostic studies. RESULTS: Seven primary studies were included in this review. All results assessed using the modified GRADE demonstrated low to very low quality evidence given the small number of studies and small sample. Three studies examined C-reactive protein (CRP), one of which found significantly higher CRP levels in an acute NSLBP group than in controls and an association between high pain intensity and elevated CRP. Three studies examined tumor necrosis factor alpha (TNF-α), two of which found elevated TNF-α in chronic NSLBP participants compared to controls. Two studies examined interleukin 6 (IL-6), none of which found a significant difference in IL-6 levels between NSLBP groups and controls. Two studies examined interleukin 1 beta (IL-ß), none of which found a significant difference in IL-ß levels between NSLBP groups and controls. CONCLUSIONS: This review found evidence of elevated CRP in individuals with acute NSLBP and elevated TNF-Α in individuals with chronic NSLBP. There are a limited number of high-quality studies evaluating similar patient groups and similar biomarkers, which limits the conclusion of this review.

Growth and differentiation factor 15 is a biomarker for low back pain-associated disability.

The development of low back pain (LBP) is often associated with obesity and sarcopenia. However, the mechanisms of this association remain unclear. To clarify this, we measured circulating levels of a selected panel of soluble factors, presumably involved in obesity and sarcopenia pathogenesis, and correlated them with several LBP-related characteristics, taking into account body composition and other relevant covariates. In the cross-sectional study of 1078 individuals, we collected data on self-reported LBP, body composition (including fat and skeletal muscle mass) assessed by the bioimpedance method and anthropometrically, and measured plasma levels of several cytokines by ELISA. In the statistical analysis, we took into account familial composition of the sample and possible putative genetic effects. We report that LBP-affected individuals were significantly older, with increased obesity and decreased skeletal mass, respectively, compared with the non-affected group. In univariate analyses, plasma concentrations of Growth and differentiation factor 15 (GDF-15), leptin, chemerin and follistatin were found significantly elevated in the LBP-affected groups (with or without sciatic pain) and were highly significantly (p < 0.001) associated with other LBP-related phenotypes, specifically, disease duration, disability and physician consults. However, after adjustment for one another, age, sex, body composition and putative genetic factors, the only associations between GDF-15 and LBP disability and medical consulting phenotypes, remained significant. In conclusion, we report for the first time, a significant and independent association between plasma GDF-15 concentrations and LBP-associated disability. Longitudinal studies are needed to determine whether GDF-15 could be a novel therapeutic target for prevention and/or treatment of LBP.

LINC00311 is overexpressed in ankylosing spondylitis and predict treatment outcomes and recurrence.

BACKGROUND: LncRNA LINC00311 participates in osteoporosis, which shows inverse pathological changes to ankylosing spondylitis (AS), indicating that LINC00311 is also involved in AS. METHODS: All the participants were enrolled in Ganzhou People's Hospital between January 2016 and January 2018 after this study was approved by Ganzhou People's Hospital Ethics Committee. Disease activity determination, follow-up and RT-qPCR were carried out during the research. RESULTS: In the present study we found that LINC00311 was upregulated in AS patients comparing to healthy controls, and upregulation of LINC00311 distinguished AS patients from healthy controls. LINC00311 expression levels were positively correlated with disease activity. Comparing to pre-treatment levels, LINC00311 expression level decreased significantly after treatment. During 2-year follow-up, patients with high levels of LINC00311 showed a significantly higher rate of rehospitalization. CONCLUSIONS: Therefore, LINC00311 is overexpressed in AS and predict treatment outcomes and recurrence.

Inflammatory biomarkers do not distinguish between patients with sciatica and referred leg pain within a primary care population: results from a nested study within the ATLAS cohort.

BACKGROUND: There is increasing interest in the role of pro-inflammatory cytokines in the pathogenesis of sciatica and whether these could be potential targets for treatment. We sought to investigate serum biomarker levels in patients with low back-related leg pain, including sciatica. METHODS: Primary care consulters aged > 18 with low back-related leg pain were recruited to a cohort study (ATLAS). Participants underwent a standardised clinical assessment, lumbar spine MRI and a subsample (n = 119) had samples taken for biomarker analysis. Participants were classified having: a) clinically confirmed sciatica or referred leg pain, and then subdivided into those with (or without) MRI confirmed nerve root compression due to disc prolapse. Seventeen key cytokines, chemokines and matrix metalloproteinases (MMPs) implicated in sciatica pathogenesis including TNFα and IL-6, were assayed in duplicate using commercial multiplex detection kits and measured using a Luminex suspension array system. Median biomarker levels were compared between the groups using a Mann Whitney U test. Multivariate logistic regression analysis was used to investigate the association between clinical measures and biomarker levels adjusted for possible confounders such as age, sex, and symptom duration. RESULTS: No difference was found in the serum level of any of the 17 biomarkers tested in patients with (n = 93) or without (n = 26) clinically confirmed sciatica, nor between those with (n = 44) or without (n = 49) sciatica and MRI confirmed nerve root compression. CONCLUSION: In this cohort, no significant differences in serum levels of TNFα, IL-6 or any other biomarkers were seen between patients with sciatica and those with back pain with referred leg pain. These results suggest that in patients with low back-related leg pain, serum markers associated with inflammation do not discriminate between patients with or without clinically confirmed sciatica or between those with or without evidence of nerve root compression on MRI.

Study of Humoral Immunity Indicators for Evaluation of Chronic Pain State.

Variation of natural antibody (nAb) levels to the pain bioregulators (ß-endorphin, orphanin, serotonin, dopamine, histamine, and angiotensin) in blood serum at chronic low back pain (LBP) was studied for 21 days. We revealed gender features of immuno-profiles: more elevated nAb levels in women at 1st day and equal levels in gender groups at 21st day. In addition, nAb levels remained above normal up to day 21 in most of patients despite a threefold decrease in pain intensity, measured using a differential visual analogue scale. A significant decrease in nAb levels was found in 4-20% of patients depending on the bioregulator. These observations support the hypothesis that antibodies can be a factor in the prolongation of pain. Therefore, the analysis of the dynamics of nAbs can be recommended for patients with LBP, from which it is possible to predict the further course of the disease.

Therapeutic Effect of Medical Ozone on Lumbar Disc Herniation.

BACKGROUND This study aimed to investigate the therapeutic effect of low, medium, and high concentrations of medical ozone on trauma-induced lumbar disc herniation. MATERIAL AND METHODS A total of 80 patients were included and were grouped into a control group, a low medical ozone (20 µg/ml) group, a medium medical ozone (40 µg/ml) group, and a high medical ozone (60 µg/ml) group. The CT scan and enzyme-linked immunosorbent assay (ELISA) were used to detect IL-6 level, SOD activity, IgM, and IgG levels upon admission and at 6 and 12 months after follow-up. The area under the ROC curve (AUC) was calculated for visual analogue scale (VAS) and efficiency rate. RESULTS All patients showed disc retraction at 6- and 12-month follow-up; while patients in the medium medical ozone (40 µg/ml) group showed the greatest disc retraction rate. The IL-6, IgM, IgG, and VAS levels significantly decreased while SOD activity increased among all groups over time (p<0.05). The AUCIL-6, AUCIgG, AUCIgM, and AUCSOD was closest to 1 in the medium medical ozone (40 µg/ml) group compared with other groups (p<0.01), with the highest efficacy at 6 (35%) and 12 (85%) months during follow-up. CONCLUSIONS Low concentrations of medical ozone (20 µg/ml and 40 µg/ml) reduced the serum IL-6, IgG, and IgM expression, presenting as analgesic and anti-inflammatory effects, while high concentrations of medical ozone (60 µg/ml) increased the serum IL-6, IgG, IgM expression, presenting as pain and pro-inflammatory effects. The medical ozone concentration of 40 µg/ml showed the optimal treatment efficacy.

Association between serum lipids and low back pain among a middle-aged Japanese population: a large-scale cross-sectional study.

BACKGROUND: Abnormal lipid levels have been suggested as a mechanism leading to atherosclerosis of the lumbar vessels, resulting in low back pain (LBP). This study examined whether abnormal lipid levels were associated with LBP among middle-aged adults in Japan. METHODS: The present study included adults between 40 and 64 years old who underwent an annual health checkup. A total of 258,367 eligible participants were analyzed to investigate associations of LBP with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and LDL-C/HDL-C ratio. Participants were categorized into two groups according to each of LDL-C, HDL-C, and LDL-C/HDL-C ratio (LDL-C: ≥ 140 vs. < 140 mg/dL; HDL-C: ≥ 40 vs. < 40 mg/dL; LDL-C/HDL-C ratio: ≥ 2.5 vs. < 2.5). Information on LBP was obtained using a self-administered questionnaire. Logistic regression modeling was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for LBP. RESULTS: The prevalence of LBP was 2.2% in men and 2.1% in women. Multivariable analysis adjusting for age, body mass index, and lifestyle factors found significant associations for HDL-C <  40 mg/dL (OR, 1.34; 95%CI, 1.20-1.48 in men; OR, 1.32; 95%CI, 1.02-1.72 in women) and LDL-C/HDL-C ratio ≥ 2.5 (OR, 1.17; 95%CI, 1.09-1.26 in men; OR, 1.15; 95%CI, 1.03-1.29 in women) with LBP. CONCLUSIONS: Low HDL-C and high LDL-C/HDL-C ratio were significantly associated with LBP in a middle-aged Japanese population. These findings might support the atherosclerosis-LBP hypothesis.

ISSLS PRIZE IN CLINICAL SCIENCE 2018: longitudinal analysis of inflammatory, psychological, and sleep-related factors following an acute low back pain episode-the good, the bad, and the ugly.

STUDY DESIGN: Prospective longitudinal study. OBJECTIVE: To determine whether systemic cytokines and C-reactive protein (CRP) during an acute episode of low back pain (LBP) differ between individuals who did and did not recover by 6 months and to identify sub-groups based on patterns of inflammatory, psychological, and sleep features associated with recovery/non-recovery. Systemic inflammation is observed in chronic LBP and may contribute to the transition from acute to persistent LBP. Longitudinal studies are required to determine whether changes present early or develop over time. Psychological and/or sleep-related factors may be related. METHODS: Individuals within 2 weeks of onset of acute LBP (N = 109) and pain-free controls (N = 55) provided blood for assessment of CRP, tumor necrosis factor (TNF), interleukin-6 (IL-6) and interleukin-1ß, and completed questionnaires related to pain, disability, sleep, and psychological status. LBP participants repeated measurements at 6 months. Biomarkers were compared between LBP and control participants at baseline, and in longitudinal (baseline/6 months) analysis, between unrecovered (≥pain and disability), partially recovered (reduced pain and/or disability) and recovered (no pain and disability) participants at 6 months. We assessed baseline patterns of inflammatory, psychological, sleep, and pain data using hierarchical clustering and related the clusters to recovery (% change in pain) at 6 months. RESULTS: CRP was higher in acute LBP than controls at baseline. In LBP, baseline CRP was higher in the recovered than non-recovered groups. Conversely, TNF was higher at both time-points in the non-recovered than recovered groups. Two sub-groups were identified that associated with more ("inflammatory/poor sleep") or less ("high TNF/depression") recovery. CONCLUSIONS: This is the first evidence of a relationship between an "acute-phase" systemic inflammatory response and recovery at 6 months. High inflammation (CRP/IL-6) was associated with good recovery, but specific elevation of TNF, along with depressive symptoms, was associated with bad recovery. Depression and TNF may have a two-way relationship. These slides can be retrieved under Electronic Supplementary Material.

Systemic inflammatory profiles and their relationships with demographic, behavioural and clinical features in acute low back pain.

Systemic inflammation is linked with development and persistence of many pathological pain states. Although chronic phase inflammatory responses are well reported, the acute phase has received limited attention. Here we investigated circulating pro-inflammatory cytokines and C-reactive protein (CRP), and explored their relationships with symptom severity and other factors in acute low back pain (LBP). Ninety-nine individuals within two weeks of onset of acute LBP and 55 pain-free controls completed questionnaires related to their pain (visual analogue scale, VAS) and disability, behaviour, sleep quality and psychological status. CRP, interleukin-6 (IL-6), tumor necrosis factor (TNF) and interleukin-1ß (IL-1ß) were measured from serum samples. Biomarkers were compared between LBP and control participants, and in a separate analysis, for those with "high-pain" (VAS ⩾4) and "low-pain" (VAS <4). The relationships between biomarkers and all other variables, including other cytokines/CRP were assessed. CRP was higher in LBP than controls and in those with high- than low-pain (p<0.01). IL-6 was higher in those with high- than low-pain (p<0.05), but not controls. Various pain and non-pain factors were associated with each biomarker differently. These findings suggest systemic CRP and IL-6 are important contributors to inflammation in the early post-onset phase of LBP and that various factors can shape these responses.

The serum concentrations of leptin and MCP-1 independently predict low back pain duration.

BACKGROUND: Low back pain (LBP) is a very frequent condition, affecting most people at some point throughout their life. This cross-sectional study was aimed to investigate a selected panel of cytokines and inflammatory biomarkers in patients with or without LBP. METHODS: The study population consisted of 104 patients diagnosed with LBP (52 non-persistent and 52 persistent) and 52 healthy subjects with no LBP. Blood samples were collected for assessment of adiponectin, leptin, monocyte chemoattractant protein-1 (MCP-1) and C reactive protein (CRP). The duration of LBP was categorized as "no pain", "non-persistent LBP" and "persistent LBP". RESULTS: Higher values of CRP and lower concentrations of both leptin and MCP-1 were found in LBP patients compared to controls, whereas adiponectin did not differ among groups. MCP-1 was also lower in patients with non-persistent than in those with persistent LBP. Age, leptin (relative risk, 11.8; 95% CI, 3.9-35.8) and MCP-1 (relative risk, 2.7; 95% CI, 1.7-4.4) were independently associated with presence and duration of LBP. The combination of age, leptin and MCP-1 predicted 61% of the risk of LBP duration. The area under the curve of MCP-1 for distinguishing persistent from non-persistent LBP was 0.65 (95% CI, 0.54-0.76). CONCLUSIONS: Then results of our study suggest that leptin and MCP-1 may be promising biomarkers for diagnosis of acute LBP and its risk to become chronic.

Circulating Lipids and Acute Pain Sensitization: An Exploratory Analysis.

BACKGROUND: In individuals with low back pain, higher lipid levels have been documented and were associated with increased risk for chronic low back pain. OBJECTIVES: The purpose of this research was to identify plasma lipids that discriminate participants with acute low back pain with or without pain sensitization as measured by quantitative sensory testing. METHODS: This exploratory study was conducted as part of a larger parent randomized controlled trial. A cluster analysis of 30 participants with acute low back pain revealed two clusters: one with signs of peripheral and central sensitivity to mechanical and thermal stimuli and the other with an absence of peripheral and central sensitivity. Lipid levels were extracted from plasma and measured using mass spectroscopy. RESULTS: Triacylglycerol 50:2 was significantly higher in participants with peripheral and central sensitization compared to the nonsensitized cluster. The nonsensitized cluster had significantly higher levels of phosphoglyceride 34:2, plasmenyl phosphocholine 38:1, and phosphatidic acid 28:1 compared to participants with peripheral and central sensitization. Linear discriminant function analysis was conducted using the four statistically significant lipids to test their predictive power to classify those in the sensitization and no-sensitization clusters; the four lipids accurately predicted cluster classification 58% of the time (R = .58, -2 log likelihood = 14.59). DISCUSSION: The results of this exploratory study suggest a unique lipidomic signature in plasma of patients with acute low back pain based on the presence or absence of pain sensitization. Future work to replicate these preliminary findings is underway.

Differential expression of P2X7 receptor and IL-1ß in nociceptive and neuropathic pain.

BACKGROUND: Despite substantial progress, pathogenesis and therapy of chronic pain are still the focus of many investigations. The ATP-gated P2X7 receptor (P2X7R) has previously been shown to play a central role in animal models of nociceptive inflammatory and neuropathic pain. Recently, we found that the adaptive immune system is involved in the pathophysiology of chronic nociceptive and neuropathic pain in humans. So far, data regarding P2X7R expression patterns on cells of the adaptive immune system of pain patients are scarce. We therefore analyzed the P2X7R expression on peripheral blood lymphocytes and monocytes, as well as serum levels of IL-1ß in patients suffering from chronic nociceptive and neuropathic pain in comparison to healthy volunteers in order to identify individuals who might benefit from a P2X7R modulating therapy. METHODS: P2X7R messenger RNA (mRNA) and protein expression were determined in patients with either chronic nociceptive low back pain (CLBP) or neuropathic pain (NeP), and in healthy volunteers by quantitative real-time PCR (qPCR) and by fluorescence-assisted cell-sorting (FACS), respectively. IL-1ß serum levels were measured with a multiplex cytokine assay. RESULTS: Compared to healthy volunteers, P2X7R mRNA (1.6-fold, p = 0.038) and protein levels were significantly increased on monocytes (NeP: 24.6 ± 6.2, healthy volunteers: 17.0 ± 5.4; p = 0.002) and lymphocytes (NeP: 21.8 ± 6.5, healthy volunteers: 15.6 ± 5.2; p = 0.009) of patients with NeP, but not in patients with CLBP. Similarly, IL-1ß serum concentrations were significantly elevated only in NeP patients (1.4-fold, p = 0.04). CONCLUSIONS: A significant upregulation of P2X7R and increased IL-1ß release seems to be a particular phenomenon in patients with NeP. P2X7R inhibitors may therefore represent a potential option for the treatment of this frequently intractable type of pain. German Clinical Trial Register (DRKS): Registration Trial DRKS00005954.

Systemic blood plasma CCL5 and CXCL6: Potential biomarkers for human lumbar disc degeneration.

Lumbar disc degeneration severity on magnetic resonance imaging (MRI) is associated with low back pain. Pro-inflammatory chemokines CCL5 and CXCL6 are released by induced degenerative discs, and CCL5 has been associated with discogenic back pain. A case-control study was performed, based on the Hong Kong Disc Degeneration Population-Based Cohort of Southern Chinese, to investigate if systemic levels of CCL5 and CXCL6 were elevated in subjects with disc degeneration compared to non-degenerated individuals. Eighty subjects were selected, 40 with no disc degeneration (control group; DDD score 0) and 40 with moderate/severe disc degeneration (disc degeneration group; DDD score ≥5) as noted on MRI. Subjects were matched for age, sex, body mass index and workload. Blood plasma samples were obtained from each individual, and levels of CCL5 and CXCL6 were measured. Secondary phenotypes of lumbar disc displacement and cervical disc changes were also assessed. CCL5 concentrations were significantly increased in the disc degeneration (mean: 19.8 ng/mL) compared to the control group (mean: 12.8 ng/mL) (p = 0.015). The degeneration group demonstrated higher levels of CXCL6 (mean: 56.9 pg/mL) compared to the control group (mean: 43.4 pg/mL) (p = 0.010). There was a trend towards elevated CCL5 levels with disc displacement in the degeneration group (p = 0.073). Cervical disc degeneration was not associated with elevated chemokine levels (p > 0.05). This is the first study to note that elevated systemic CCL5 and CXCL6 were associated with moderate/severe lumbar disc degeneration, further corroborating tissue studies of painful discs. These chemokines may be systemic biomarkers for the diagnosis and monitoring of disc degeneration.

A cohort study comparing the serum levels of pro- or anti-inflammatory cytokines in patients with lumbar radicular pain and healthy subjects.

PURPOSE: The factors influencing the presence or absence of pain in sciatica secondary to disc herniation remain incompletely understood. We hypothesized that the imbalance in inflammatory cytokines is implicated in the generation of pain. In our study, serum levels of pro-inflammatory and anti-inflammatory cytokines were investigated among patients with severe sciatica; the serum levels were compared with those of patients with mild sciatica and healthy subjects. METHODS: In this prospective study, blood protein levels of the pro-inflammatory cytokines, namely, interleukin-6 (IL-6), interleukin-8 (IL-8),and tumor necrosis factor-α (TNF-α), and the anti-inflammatory cytokines, namely, interleukin-4 (IL-4) and interleukin-10 (IL-10), of 58 patients with severe sciatica, 50 patients with mild sciatica, and 30 healthy control subjects were analyzed through ELISA. Physical and mental health symptoms were determined using the Oswestry Disability Index (ODI) and short form-36 (SF-36) questionnaire. Spearman rank correlation coefficient was also determined to calculate the correlation between the scores obtained from the questionnaires and the serum levels of cytokines. RESULTS: IL-6 protein was detected in the three groups and median levels were about 1.5 times higher in patients with severe sciatica than the mild sciatica group (p = 0.02) and the controls (p = 0.03). Median levels of IL-8 in sciatica patients were higher than those of the healthy controls (p = 0.001 for severe sciatica, p = 0.02 for mild sciatica). The TNF-α protein values were approximately twofold higher in the severe sciatica group than in the mild sciatica group (p < 0.01) and in the healthy control group (p < 0.01). Median levels of IL-4 were about 2.5-fold higher in mild sciatica (p < 0.01) and about twofold higher in patients with severe sciatica (p = 0.012) when compared with controls. Median protein levels of IL-10 showed a trend to be higher in patients with mild sciatica compared with severe sciatica (p < 0.01) and with healthy controls (p < 0.01). ODI was significantly correlated with IL-6 (r = 0.394, p = 0.013), TNF-α (r = 0.629, p < 0.001), and IL-10 (r = -0.415, p = 0.009). ODI was not significantly correlated with IL-4 (r = -0.174, p = 0.29) and IL-8 (r = -0.133, p = 0.418). CONCLUSIONS: These findings support our hypothesis that sciatica pain is accompanied by the imbalance in inflammatory cytokines.

No association between level of vitamin D and chronic low back pain in Swedish primary care: a cross-sectional case-control study.

OBJECTIVE: Assessment of vitamin D levels and deficiency status in individuals with chronic low back pain (CLBP) in a Swedish general population, compared with controls matched for sex and age. DESIGN: Cross-sectional case-control study. SETTING: Primary care, southern Sweden. SUBJECTS: Participants (n = 44) with self-reported low back pain for at least 3 months and individually sex- and age-matched controls without a chronic pain condition (n = 44), recruited from the general population by random letter of invitation. MAIN OUTCOME MEASURE: Association between vitamin D level and CLBP when adjusting for possible confounders in a multivariate forward conditional logistic regression model. RESULTS: Mean S-25-hydroxyvitamin D levels were 81 and 80 nmol/L in the CLBP and control group, respectively. The prevalence of vitamin D deficiency was low and similar in the CLBP group and the control group. Vitamin D level was not associated with CLBP when potential confounders were taken into account. CONCLUSIONS: No difference in vitamin D levels between participants with CLBP and matched controls could be demonstrated in the present sample. Assessment of vitamin D level and deficiency status may be of questionable value in the management of CLBP in primary care settings at similar latitudes, unless there are additional risk factors for deficiency or specific indicators of osteomalacia. Key points Vitamin D deficiency is common and reported in many chronic pain conditions, including chronic low back pain (CLBP), but evidence for an association and causality is insufficient. • The present study found no association between vitamin D levels and CLBP in a case-control sample of 44 + 44 individuals from the Swedish general population. • Prevalence of vitamin D deficiency was low and comparable in individuals with CLBP and controls without chronic pain, matched for sex and age. • Assessment of vitamin D status, for the purpose of finding and treating an underlying cause of pain, may be of limited value in the management of CLBP in primary care settings at similar latitudes.

Comparison of biochemical response between the minimally invasive and standard open posterior lumbar interbody fusion.

BACKGROUND: The mini-invasive open posterior lumbar fusion procedure (mini PLIF) procedure is an alternative to standard open procedure (open PLIF) and is intended to reduce surgery-related trauma. The measuring of suitable biochemical factors enables objective comparison of the invasiveness of spinal surgery procedures. METHODS: Prospectively collected data on myoglobin, creatine kinase, interleukin-6, C-reactive protein levels and intensity of low back pain and radicular pain in one-level mini PLIF and open PLIF procedures were analysed. The mini PLIF and the open PLIF groups included 27 and 23 patients, respectively. The collection of blood samples and clinical data were performed preoperatively and on postoperative days 1, 3 and 7. The non-paired t-test was used for statistical evaluation. RESULTS: We did not found any statistically significant differences of myoglobin and creatine kinase levels between the groups. In the open PLIF group the IL-6 levels were significantly higher than in the mini PLIF group on postoperative day 3. CRP levels showed significant lower stress response in favour of the mini PLIF group on postoperative days 3 and 7. Levels of post-op low back pain on day 3 were significantly lower in mini PLIF group. Also intensity of radicular pain on day 1 and 3 were lower also mini PLIF group. CONCLUSION: The extent of myonecrosis was comparable in both techniques. The analysis of the IL-6 and CRP levels showed significantly lower systemic inflammatory response in mini PLIF technique. The mini PLIF technique provides transiently lower postoperative pain levels.

Serum levels of the pro-inflammatory interleukins 6 (IL-6) and -8 (IL-8) in patients with lumbar radicular pain due to disc herniation: A 12-month prospective study.

Earlier studies indicate that lumbar radicular pain after disc herniation may be associated with a local inflammation induced by leakage of nucleus pulposus (NP) into the spinal canal and neuroforamen. In the present study we addressed the role of two interleukins, IL-6 and IL-8 in such long-lasting lumbar radicular pain. All 127 patients were recruited from Oslo University Hospital, Ullevål, Norway. At inclusion, 6weeks and 12months, serum concentrations of IL-6 and IL-8 were analyzed by enzyme-linked immunosorbent assay (ELISA) and pain intensity was reported on a 0-10cm visual analog scale (VAS). Significantly higher levels of IL-6 and IL-8 in serum were found in patients with VAS ⩾3 at 12months, than in patient with VAS <3 at 12months (p⩽0.01, test of between-subjects effect, repeated measures ANOVA, covariates for IL-6: age, smoking; covariates for IL-8: smoking, treatment). For the first time we show that chronic lumbar radicular pain may be associated with a persistent increase of the pro-inflammatory substances IL-6 and IL-8 in serum after disc herniation.