Publications
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Vigeland, Maria Dehli; Flåm, Siri Tennebø; Vigeland, Magnus Dehli; Zucknick, Manuela; Wigemyr, Monica & Bråten, Lars Christian Haugli
[Show all 11 contributors for this article]
(2025).
Gene Expression Correlates with Disability and Pain Intensity in Patients with Chronic Low Back Pain and Modic Changes in a Sex-Specific Manner.
International Journal of Molecular Sciences.
ISSN 1661-6596.
26(2).
doi:
10.3390/ijms26020800.
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Chronic low back pain (cLBP) lacks clear physiological explanations, and the treatment options are of limited effect. We aimed to elucidate the underlying biology of cLBP in a subgroup of patients with Modic changes type I (suggestive of inflammatory vertebral bone marrow lesions) by correlating gene expression in blood with patient-reported outcomes on disability and pain intensity and explore sex differences. Patients were included from the placebo group of a clinical study on patients with cLBP and Modic changes. Blood was collected at the time of inclusion, after three months, and after one year, and gene expression was measured at all time points by high-throughput RNA sequencing. The patients reported disability using the Roland–Morris Disability Questionnaire, and pain intensity was assessed as a mean of three scores on a 0–10 numeric rating scale: current LBP, worst LBP within the last two weeks, and mean LBP within the last two weeks. The gene expression profiles were then correlated to the reported outcomes. Changes in gene expression over time correlated significantly with changes in both disability and pain. The findings showed distinct patterns in men and women, with negligible overlap in correlated genes between the sexes. The genes involved were enriched in immunological pathways, particularly T cell receptor complex and immune responses related to neutrophils. Several of the genes harbour polymorphisms that previously have been found to be associated with chronic pain. Taken together, our results indicate gender differences in the underlying biology of disability and pain intensity in patients with low back pain.
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Vigeland, Maria Dehli; Flåm, Siri Tennebø; Vigeland, Magnus Dehli; Espeland, Ansgar; Zucknick, Manuela & Wigemyr, Monica
[Show all 14 contributors for this article]
(2023).
Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes.
Antibiotics.
12(7).
doi:
10.3390/antibiotics12071217.
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Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.
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Gjefsen, Elisabeth; Gervin, Kristina; Bråten, Lars Christian Haugli; Goll, Guro Løvik; Aass, Hans Christian & Schistad, Elina Iordanova
[Show all 13 contributors for this article]
(2023).
Longitudinal changes of serum cytokines in patients with chronic low back pain and Modic changes.
Osteoarthritis and Cartilage.
ISSN 1063-4584.
31(4),
p. 543–547.
doi:
10.1016/j.joca.2023.01.001.
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Objectives: To explore serum cytokine levels over time in patients with chronic low back pain (cLBP) and Modic changes (MCs), difference in change between treatment groups in the Antibiotics in Modic Changes (AIM) study and associations between change in cytokines and low back pain. Methods: Serum concentrations of 39 cytokines were measured at baseline and 1 year from 73 partic- ipants in the AIM study; 30 randomized to placebo, 43 to Amoxicillin. Low back pain intensity was measured by numeric rating scale. Change in cytokine levels over time were assessed by paired t-tests. Difference in change in cytokine levels between treatment groups and associations between changes in LBP and cytokine levels were assessed by linear regression models. Networks of cytokine changes in each treatment groups were explored by Pearson's correlations. Results: Five cytokines changed from baseline to 1 year, (mean change, log transformed values with CI) C-X-C motif chemokine ligand (CXCL) 10 (IP-10) (0.11 (0.01e0.20)), CXCL13 (0.61 (0.00e0.12)), C-C motif chemokine ligand (CCL)26 (0.05 (0.01e0.1)), granulocyte macrophage-colony stimulating factor (GM- CSF) ( 0.12 ( 0.23 to 0.00)) and CXCL11 (0.12 (0.03e0.22)). Treatment group only influenced change in CCL21 (b 0.07 (0.01e0.12)), and IL-6 (b 0.17 ( 0.30 to 0.03)). Change in CXCL13 (b 2.43 (0.49e4.38)), CCL27 (b 3.07 (0.46e5.69)), IL-8 (b 1.83 (0.08e3.58)) and CCL19 (b 3.10 (0.86e5.43)) were associated with change in LBP. The correlation networks of cytokine changes demonstrate small differences between treatment groups. Conclusions: Cytokine levels are relatively stable over time in our sample, with little difference between treatment groups. Some cytokines may be associated with LBP intensity. The differences between the correlation networks suggest that long-term Amoxicillin-treatment may have longstanding effects to be further explored.
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Dunker, Øystein; Uglem, Martin; Kvaløy, Marie Bu; Løseth, Sissel; Hjelland, Ina Elen & Allen, Sara Maria
[Show all 10 contributors for this article]
(2023).
Diagnostic accuracy of the 5.07 monofilament test for diabetes polyneuropathy: influence of age, sex, neuropathic pain and neuropathy severity.
BMJ Open Diabetes Research & Care.
11(6).
doi:
10.1136/bmjdrc-2023-003545.
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Introduction There is a need for simple and cheap diagnostic tools for diabetic polyneuropathy (DPN). We aimed to assess the diagnostic accuracy of the 5.07/10 g monofilament test in patients referred to polyneuropathy assessments, as well as to examine how disease severity, age, sex and neuropathic pain (NP) impact diagnostic accuracy. Research design and methods Five Norwegian university hospitals recruited patients with diabetes aged 18–70 referred to neurological outpatient clinics for polyneuropathy assessments. The 5.07/10 g Semmes-Weinstein monofilament examination (SWME) was validated against the Toronto consensus for diagnosing diabetic neuropathies; the results were stratified by age, sex and NP. Disease severity was graded by a combined nerve conduction study (NCS) Z-score, and logistic regression was applied to assess whether disease severity was a predictor of diagnostic accuracy. Results In total, 506 patients were included in the study. Global sensitivity was 0.60 (95% CI 0.55, 0.66), specificity 0.82 (95% CI 0.75, 0.87), positive and negative predictive values were 0.86 (95% CI 0.81, 0.90) and 0.52 (95% CI 0.46, 0.58), respectively, positive and negative likelihood ratios were 3.28 (95% CI 2.37, 4.53) and 0.49 (95% CI 0.42, 0.57), respectively. The SWME was less sensitive in females (0.43), had lower specificity in patients with NP (0.56), and performed worse in patients ≥50 years. NCS-based disease severity did not affect diagnostic accuracy (OR 1.15, 95% CI 0.95, 1.40). Conclusions This multicenter study demonstrates poor diagnostic performance for the 5.07/10 g SWME in patients with diabetes referred to polyneuropathy assessments; it is particularly unsuited for female patients and those with NP. The diagnostic accuracy of the SWME was not influenced by NCS-based disease severity, demonstrating that it does not perform better in patients with later stages of DPN. We do not recommend the use of the 5.07/10 g monofilament in the evaluation of patients with diabetes referred to polyneuropathy assessments.
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Dunker, Øystein; Grotle, Margreth; Kvaløy, Marie Bu; Uglem, Martin; Løseth, Sissel & Hjelland, Ina Elen
[Show all 12 contributors for this article]
(2022).
Accuracy of neuropathic pain measurements in patients with symptoms of polyneuropathy: validation of painDETECT, Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs, and Douleur Neuropathique 4.
Pain.
ISSN 0304-3959.
164(5),
p. 991–1001.
doi:
10.1097/j.pain.0000000000002793.
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Pain is a common symptom in patients referred to polyneuropathy assessment. Diagnostic evaluation and choice of treatment may depend on whether the pain is likely to be neuropathic or not. This study aimed to investigate the diagnostic accuracy of 3 tools commonly used to differentiate between neuropathic and nonneuropathic pain. To accomplish this, we included patients with bilateral distal lower extremity pain, referred to neurological outpatient clinics at 5 Norwegian University hospitals for polyneuropathy assessment. The patients filled in Norwegian versions of painDETECT, the Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), and the clinician-rated Douleur Neuropathique 4 (DN4). All patients underwent a clinical examination and nerve conduction measurements and were classified according to the NeuPSIG neuropathic pain criteria (reference standard). In total, 729 patients were included, of which 63% had neuropathic pain by the reference standard. Only DN4 demonstrated high sensitivity (0.87), whereas all 3 tools had low specificity (≤0.65). Importantly, the tools' predictive ability was unsatisfactory; The probability of getting a correct test result was 3 quarters at best, and at worst, no better than two fifths. Consequently, we show that neither DN4, painDETECT, nor S-LANSS can be confidently used to assess neuropathic pain in a neurological outpatient population with symptoms of polyneuropathy.
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Vigeland, Maria Dehli; Flåm, Siri Tennebø; Vigeland, Magnus Dehli; Espeland, Ansgar; Kristoffersen, Per Martin & Vetti, Nils
[Show all 17 contributors for this article]
(2022).
Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement.
Scientific Reports.
12(1),
p. 1–12.
doi:
10.1038/s41598-021-04189-5.
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Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.
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Gjefsen, Elisabeth; Gervin, Kristina; Goll, Guro Løvik; Bråten, Lars Christian Haugli; Wigemyr, Monica & Aass, Hans Christian Dalsbotten
[Show all 13 contributors for this article]
(2021).
Macrophage migration inhibitory factor: A potential biomarker for chronic low back pain in patients with Modic changes.
RMD Open.
7(2),
p. 1–10.
doi:
10.1136/rmdopen-2021-001726.
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Background: Low back pain (LBP) is a leading cause of disability worldwide, but the aetiology remains poorly understood. Finding relevant biomarkers may lead to better understanding of disease mechanisms. Patients with vertebral endplate bone marrow lesions visualised on MRI as Modic changes (MCs) have been proposed as a distinct LBP phenotype, and inflammatory mediators may be involved in the development of MCs. Objectives: To identify possible serum biomarkers for LBP in patients with MCs. Methods: In this case control study serum levels of 40 cytokines were compared between patients with LBP and MC type 1 (n=46) or type 2 (n=37) and healthy controls (n=50). Results: Analyses identified significantly higher levels of six out of 40 cytokines in the MC type 1 group (MC1), and five in the MC type 2 group (MC2) compared with healthy controls. Six cytokines were moderately correlated with pain. Principal component analyses revealed clustering and separation of patients with LBP and controls, capturing 40.8% of the total variance, with 10 cytokines contributing to the separation. Macrophage migration inhibitory factor (MIF) alone accounted for 92% of the total contribution. Further, receiver operating characteristics analysis revealed that MIF showed an acceptable ability to distinguish between patients and controls (area under the curve=0.79). Conclusions: These results suggest that cytokines may play a role in LBP with MCs. The clinical significance of the findings is unknown. MIF strongly contributed to clustering of patients with LBP with MCs and controls and might be a biomarker for MCs. Ultimately, these results may guide future research on novel treatments for this patient group.
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Bråten, Lars Christian Haugli; Rolfsen, Mads Peder; Espeland, Ansgar; Wigemyr, Monica; Assmus, Jörg & Froholdt, Anne
[Show all 28 contributors for this article]
(2019).
Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial.
The BMJ.
367.
doi:
10.1136/bmj.l5654.
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Objective
To assess the efficacy of three months of antibiotic treatment compared with placebo in patients with chronic low back pain, previous disc herniation, and vertebral endplate changes (Modic changes).
Design
Double blind, parallel group, placebo controlled, multicentre trial.
Setting
Hospital outpatient clinics at six hospitals in Norway.
Participants
180 patients with chronic low back pain, previous disc herniation, and type 1 (n=118) or type 2 (n=62) Modic changes enrolled from June 2015 to September 2017.
Interventions
Patients were randomised to three months of oral treatment with either 750 mg amoxicillin or placebo three times daily. The allocation sequence was concealed by using a computer generated number on the prescription.
Main outcome measures
The primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (range 0-24) at one year follow-up in the intention to treat population. The minimal clinically important between group difference in mean RMDQ score was predefined as 4.
Results
In the primary analysis of the total cohort at one year, the difference in the mean RMDQ score between the amoxicillin group and the placebo group was −1.6 (95% confidence interval −3.1 to 0.0, P=0.04). In the secondary analysis, the difference in the mean RMDQ score between the groups was −2.3 (−4.2 to−0.4, P=0.02) for patients with type 1 Modic changes and −0.1 (−2.7 to 2.6, P=0.95) for patients with type 2 Modic changes. Fifty patients (56%) in the amoxicillin group experienced at least one drug related adverse event compared with 31 (34%) in the placebo group.
Conclusions
In this study on patients with chronic low back pain and Modic changes at the level of a previous disc herniation, three months of treatment with amoxicillin did not provide a clinically important benefit compared with placebo. Secondary analyses and sensitivity analyses supported this finding. Therefore, our results do not support the use of antibiotic treatment for chronic low back pain and Modic changes.
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Published
Nov. 18, 2024 3:52 PM
- Last modified
Nov. 18, 2024 3:52 PM
