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Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement.

ABSTRACT: 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.

SUBMITTER: Vigeland MD

PROVIDER: S-EPMC8741947 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement.

Vigeland Maria Dehli MD Flåm Siri Tennebø ST Vigeland Magnus Dehli MD Espeland Ansgar A Kristoffersen Per Martin PM Vetti Nils N Wigemyr Monica M Bråten Lars Christian Haugli LCH Gjefsen Elisabeth E Schistad Elina Iordanova EI Haugen Anne Julsrud AJ Froholdt Anne A Skouen Jan Sture JS Zwart John-Anker JA Storheim Kjersti K Pedersen Linda Margareth LM Lie Benedicte Alexandra BA

Scientific reports 20220107 1

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 invers ...[more]

PMID: 34997115

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Project description:ObjectiveTo evaluate potential MRI-defined effect modifiers of amoxicillin treatment in patients with chronic low back pain and type 1 or 2 Modic changes (MCs) at the level of a previous lumbar disc herniation (index level).MethodsIn a prospective trial (AIM), 180 patients (25-64 years; mean age 45; 105 women) were randomised to receive amoxicillin or placebo for 3 months. Primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (0-24 scale) at 1 year. Mean RMDQ score difference between the groups at 1 year defined the treatment effect; 4 RMDQ points defined the minimal clinically important effect. Predefined baseline MRI features of MCs at the index level(s) were investigated as potential effect modifiers. The predefined primary hypothesis was a better effect of amoxicillin when short tau inversion recovery (STIR) shows more MC-related high signal. To evaluate this hypothesis, we pre-constructed a composite variable with three categories (STIR1/2/3). STIR3 implied MC-related STIR signal increases with volume ≥ 25% and height > 50% of vertebral body and maximum intensity increase ≥ 25% and presence on both sides of the disc. As pre-planned, interaction with treatment was analysed using ANCOVA in the per protocol population (n = 155).ResultsThe STIR3 composite group (n = 41) and STIR signal volume ≥ 25% alone (n = 45) modified the treatment effect of amoxicillin. As hypothesised, STIR3 patients reported the largest effect (- 5.1 RMDQ points; 95% CI - 8.2 to - 1.9; p for interaction = 0.008).ConclusionsPredefined subgroups with abundant MC-related index-level oedema on STIR modified the effect of amoxicillin. This finding needs replication and further support.Key points• In the primary analysis of the AIM trial, the effect of amoxicillin in patients with chronic low back pain and type 1 or 2 MCs did not reach the predefined cut-off for clinical importance. • In the present MRI subgroup analysis of AIM, predefined subgroups with abundant MC-related oedema on STIR reported an effect of amoxicillin. • This finding requires replication and further support.

Project description:BackgroundPrevious systematic reviews have reported positive associations between Modic changes (MCs) and low back pain (LBP), but due to their narrow scope and new primary studies, there is a need for a comprehensive systematic review. Our objectives were to investigate if MCs are associated with non-specific LBP and/or activity limitation and if such associations are modified by other factors.MethodsA protocol for this review was registered at PROSPERO prior to commencing the work (PROSPERO record: CRD42015017350). The MEDLINE, CINAHL and EMBASE databases were searched for relevant studies from first record to June 15th 2016. Prospective or retrospective cross-sectional cohort studies and case-control studies including people of all ages from general, working and clinical study populations were eligible for inclusion. Risk of bias assessment and data extraction for associations and potential modifiers were completed independently by pairs of reviewers. Meta-analysis was performed for homogeneous studies and presented as odds ratios (OR) with 95% CI.ResultsIn all, 5210 citations were identified and 31 studies were included. One study had low risk of bias. Fifteen studies (48%) reported statistically significant positive associations between MCs and LBP and one study found a statistically significant negative association. Meta-analysis performed for studies using concordant pain with provocative discography as the clinical outcome resulted in an OR of 4.01 (1.52-10.61). One of seven studies reported a statistically significant positive association between MCs and activity limitation. Lumbar disc level and disc degeneration were found to modify the association between MCs and LBP.ConclusionsThe results from this comprehensive systematic review indicate that the associations between MCs and LBP-related outcomes are inconsistent. The high risk of bias and the heterogeneity in terms of study samples, clinical outcomes and prevalence estimates of MCs and LBP may explain these findings. It is likely that new studies with low risk of bias will affect the direction and strength of these associations.

Project description:BackgroundModic changes (MC) are associated with low back pain (LBP). In this study, we compared changes in size and type of MC, after a single intravenous infusion of 5 mg zoledronic acid (ZA) or placebo, among chronic LBP patients with MC on magnetic resonance imaging (MRI), and evaluated whether the MRI changes correlate with symptoms.MethodsAll patients (N = 19 in ZA, 20 in placebo) had MRI at baseline (0.23-1.5 T) and at one year (1.5-3 T). We evaluated the level, type and volume of all the MC. The MC were classified into M1 (M1 (100%)), predominating M1 (M1/2 (65:35%)) or predominating M2 (M1/2 (35:65%)), and M2 (M2 (100%)). The first two were considered M1-dominant, and the latter two M2-dominant. Volumes of M1 and M2 were calculated separately for the primary MC, which was assumed to cause the symptoms, and the other MC. We analysed the one-year treatment differences in M1 and M2 volumes using analysis of covariance with adjustments for age, sex, body mass index, and smoking. The correlations between the MRI changes and the changes in LBP symptoms were analysed using Pearson correlations.ResultsIn the ZA group, 84.2% of patients had M1-dominant primary MC at baseline, compared to 50% in the placebo group (p = 0.041). The primary MC in the ZA group converted more likely to M2-dominant (42.1% ZA, 15% placebo; p = 0.0119). The other MC (15 ZA, 8 placebo) were on average 42% smaller and remained largely M2-dominant. The M1 volume of the primary MC decreased in the ZA group, but increased in the placebo group (-0.83 cm3 vs 0.91 cm3; p = 0.21). The adjusted treatment difference for M1 volume was -1.9 cm3 (95% CI -5.0 to 1.2; p = 0.22) and for M2 volume 0.23 cm3 (p = 0.86). In the MC that remained M1-dominant, volume change correlated positively with increased symptoms in the placebo group, whereas the correlations were negative and weak in the ZA group.ConclusionsZoledronic acid tended to speed up the conversion of M1-dominant into M2-dominant MC and decrease the volume of M1-dominant MC, although statistical significance was not demonstrated.Trial registrationThe registration number in ClinicalTrials.gov is NCT01330238 and the date of registration February 11, 2011.

Project description:BackgroundNo previous clinical trials have investigated MRI findings as effect modifiers for conservative treatment of low back pain. This hypothesis-setting study investigated if MRI findings modified response to rest compared with exercise in patients with chronic low back pain and Modic changes.MethodsThis study is a secondary analysis of a randomised controlled trial comparing rest with exercise. Patients were recruited from a specialised outpatient spine clinic and included in a clinical trial if they had chronic low back pain and an MRI showing Modic changes. All patients received conservative treatment while participating in the trial. Five baseline MRI findings were investigated as effect modifiers: Modic changes Type 1 (any size), large Modic changes (any type), large Modic changes Type 1, severe disc degeneration and large disc herniation. The outcome measure was change in low back pain intensity measured on a 0-10 point numerical rating scale at 14-month follow-up (n = 96). An interaction ≥ 1.0 point (0-10 scale) between treatment group and MRI findings in linear regression was considered clinically important.ResultsThe interactions for Modic Type 1, with large Modic changes or with large Modic changes Type 1 were all potentially important in size (-0.99 (95 % CI -3.28 to 1.29), -1.49 (-3.73 to 0.75), -1.49 (-3.57 to 0.58), respectively) but the direction of the effect was the opposite to what we had hypothesized-that people with these findings would benefit more from rest than from exercise. The interactions for severe disc degeneration (0.74 (-1.40 to 2.88)) and large disc herniation (-0.92 (3.15 to 1.31)) were less than the 1.0-point threshold for clinical importance. As expected, because of the lack of statistical power, no interaction term for any of the MRI findings was statistically significant.ConclusionsThree of the five MRI predictors showed potentially important effect modification, although the direction of the effect was surprising and confidence intervals were wide so very cautious interpretation is required. Further studies with adequate power are warranted to study these and additional MRI findings as potential effect modifiers for common interventions.

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Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement.

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Correlation between gene expression and MRI STIR signals in patients with chronic low back pain and Modic changes indicates immune involvement.

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