Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes

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.publishedVersio

Cost–utility analysis of antibiotic treatment in patients with chronic low back pain and Modic changes: results from a randomised, placebo-controlled trial in Norway (the AIM study)

Objective To evaluate the cost–utility of 100 days of antibiotics in patients with chronic low back pain (LBP) and type I or II Modic changes included in the Antibiotic treatment In patients with chronic low back pain and Modic changes (AIM) study. Design A cost–utility analysis from a societal and healthcare perspective alongside a double-blinded, parallel group, placebo, multicentre trial. Setting Hospital outpatient clinics at six hospitals in Norway. The main results from the AIM study showed a small effect in back-related disability in favour of the antibiotics group, and slightly larger in those with type I Modic changes, but this effect was below the pre-defined threshold for clinically relevant effect. Participants 180 patients with chronic LBP, previous disc herniation and Modic changes type I (n=118) or type II (n=62) were randomised to antibiotic treatment (n=89) or placebo-control (n=91). Interventions Oral treatment with either 750 mg amoxicillin or placebo three times daily for 100 days. Main outcome measures Quality-adjusted life years (QALYs) by EuroQoL-5D over 12 months and costs for healthcare and productivity loss measured in Euro (€1=NOK 10), in the intention-to-treat population. Cost–utility was expressed in incremental cost-effectiveness ratio (ICER). Results Mean (SD) total cost was €21 046 (20 105) in the amoxicillin group and €19 076 (19 356) in the placebo group, mean difference €1970 (95% CI; −3835 to 7774). Cost per QALY gained was €24 625. In those with type I Modic changes, the amoxicillin group had higher healthcare consumption than the placebo group, resulting in €39 425 per QALY gained. Given these ICERs and a willingness-to-pay threshold of €27 500 (NOK 275 000), the probability of amoxicillin being cost-effective was 51%. Even when the willingness-to-pay threshold increased to €55 000, the probability of amoxicillin being cost-effective was never higher than 53%. Conclusions Amoxicillin treatment showed no evidence of being cost-effective for people with chronic LBP and Modic changes during 1-year follow-up.publishedVersio

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

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.publishedVersio

Smerteopplevelse og fremkalte kortikale responser ved elektrisk stimulering - en studie blant sykepleiere i tredelt skift

Bakgrunn: Nær en fjerdedel av alle yrkesaktive i Norge arbeider skift- eller turnusarbeid, med høyest andel i helse- og sosialsektoren. Flere helseutfordringer knyttes til det å arbeide i ulike skiftordninger, hvor søvnproblemer er antatt å være den største utfordringen. I Norge rapporterer mellom 32 og 37 % av alle sykepleiere søvnproblemer knyttet til arbeidstidsordningen. Søvn og søvnproblemer er vist å ha sammenheng med smerter, men om en arbeidsrelatert søvnforstyrrelse kan være en mulig risikofaktor for muskelskjelettsmerter er derimot ukjent. Tidligere studier har vist at vedvarende søvnproblemer og muskelskjelettsmerter kan øke risikoen for langvarig sykefravær og uførhet. Kunnskap rundt konsekvensen av arbeidsrelaterte søvnforstyrrelser på plager i muskel- og skjelettsystemet er derfor nyttig i arbeidet mot lavere sykefravær i helse- og sosialsektoren. Formål: Formålet med studien var å undersøke om subjektiv smerteopplevelse og fremkalte kortikale responser etter elektrisk smertestimulering endret seg etter at forsøkspersonene hadde arbeidet to nattevakter, sammenliknet med etter to netter normalsøvn. Studien ønsket også å undersøke om en eventuell økt smertesensitivitet etter to nattevakter kan ha en sammenheng med negative forventninger. Materiale og metode: Forsøket var et enkelt blindet laboratorieeksperiment med overkrysningsdesign. Tjueåtte selvrapporterte friske sykepleiere (22 kvinner og 6 menn) deltok i forsøket ved to ulike søvnbetingelser, etter to netter normalsøvn og etter to nattevakter. Rekkefølgen på søvnbetingelsene varierte mellom forsøkspersonene. Smertesensitivitet ble undersøkt ved bruk av elektrisk smertestimulering. Ved hver forsøksdag mottok forsøkspersonene totalt 60 smertefulle stimuleringer. For å undersøke om negative forventninger (nocebo) til intensiteten av smertestimuli ble påvirket av søvn, ble enkelte av de smertefulle stimuleringene signalisert som sterkere enn hva den virkelige intensiteten var. Subjektiv smerteopplevelse ble scoret på visuell analog skala (VAS), mens fremkalte kortikale responser ble registret ved bruk av elektroencefalografi (EEG). Resultater: Subjektiv smerteopplevelse ved elektrisk smertestimulering økte signifikant etter to nattevakter, sammenliknet med etter to netter normalsøvn (p = 0,01), mens fremkalte kortikale responser var uendret (p = 0,80). Det ble ikke funnet noen interaksjon mellom søvn og nocebo for verken subjektiv smerteopplevelse (p = 0,74) eller fremkalte kortikale responser (p = 0,53) etter elektrisk smertestimulering. Konklusjon: Subjektiv smerteopplevelse etter elektrisk smertestimulering økte etter to nattevakter sammenliknet med etter to netter normalsøvn. Det var ingen endringer i fremkalte kortikale responser etter to nattevakter. Forsøkspersonenes forventning til økt smerteintensitet kan ikke forklare økningen i den subjektive smerteopplevelsen etter to nattevakter

Subjective pain ratings and event-related potentials after electrical stimulation - a study of nurses working rotating shift

Bakgrunn: Nær en fjerdedel av alle yrkesaktive i Norge arbeider skift- eller turnusarbeid, med høyest andel i helse- og sosialsektoren. Flere helseutfordringer knyttes til det å arbeide i ulike skiftordninger, hvor søvnproblemer er antatt å være den største utfordringen. I Norge rapporterer mellom 32 og 37 % av alle sykepleiere søvnproblemer knyttet til arbeidstidsordningen. Søvn og søvnproblemer er vist å ha sammenheng med smerter, men om en arbeidsrelatert søvnforstyrrelse kan være en mulig risikofaktor for muskelskjelettsmerter er derimot ukjent. Tidligere studier har vist at vedvarende søvnproblemer og muskelskjelettsmerter kan øke risikoen for langvarig sykefravær og uførhet. Kunnskap rundt konsekvensen av arbeidsrelaterte søvnforstyrrelser på plager i muskel- og skjelettsystemet er derfor nyttig i arbeidet mot lavere sykefravær i helse- og sosialsektoren. Formål: Formålet med studien var å undersøke om subjektiv smerteopplevelse og fremkalte kortikale responser etter elektrisk smertestimulering endret seg etter at forsøkspersonene hadde arbeidet to nattevakter, sammenliknet med etter to netter normalsøvn. Studien ønsket også å undersøke om en eventuell økt smertesensitivitet etter to nattevakter kan ha en sammenheng med negative forventninger. Materiale og metode: Forsøket var et enkelt blindet laboratorieeksperiment med overkrysningsdesign. Tjueåtte selvrapporterte friske sykepleiere (22 kvinner og 6 menn) deltok i forsøket ved to ulike søvnbetingelser, etter to netter normalsøvn og etter to nattevakter. Rekkefølgen på søvnbetingelsene varierte mellom forsøkspersonene. Smertesensitivitet ble undersøkt ved bruk av elektrisk smertestimulering. Ved hver forsøksdag mottok forsøkspersonene totalt 60 smertefulle stimuleringer. For å undersøke om negative forventninger (nocebo) til intensiteten av smertestimuli ble påvirket av søvn, ble enkelte av de smertefulle stimuleringene signalisert som sterkere enn hva den virkelige intensiteten var. Subjektiv smerteopplevelse ble scoret på visuell analog skala (VAS), mens fremkalte kortikale responser ble registret ved bruk av elektroencefalografi (EEG). Resultater: Subjektiv smerteopplevelse ved elektrisk smertestimulering økte signifikant etter to nattevakter, sammenliknet med etter to netter normalsøvn (p = 0,01), mens fremkalte kortikale responser var uendret (p = 0,80). Det ble ikke funnet noen interaksjon mellom søvn og nocebo for verken subjektiv smerteopplevelse (p = 0,74) eller fremkalte kortikale responser (p = 0,53) etter elektrisk smertestimulering. Konklusjon: Subjektiv smerteopplevelse etter elektrisk smertestimulering økte etter to nattevakter sammenliknet med etter to netter normalsøvn. Det var ingen endringer i fremkalte kortikale responser etter to nattevakter. Forsøkspersonenes forventning til økt smerteintensitet kan ikke forklare økningen i den subjektive smerteopplevelsen etter to nattevakter.M-FO

Macrophage migration inhibitory factor: A potential biomarker for chronic low back pain in patients with Modic changes

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

Minimal important change was on the lower spectrum of previous estimates and responsiveness was sufficient for core outcomes in chronic low back pain

Objectives: The objective of this study was to estimate the minimal important change (MIC) and responsiveness of core patient reported outcome measures for chronic low back pain (LBP) and Modic changes. Study Design and Setting: In the Antibiotics in Modic changes (AIM) trial we measured disability (RMDQ, ODI), LBP intensity (NRS) and health-related quality of life (EQ5D) electronically at baseline, three- and 12-month follow-up. MICs were estimated using Receiver Operating Curve (ROC) curve and Predictive modeling analyses against the global perceived effect. Credibility of the estimates was assessed by a standardized set of criteria. Responsiveness was assessed by a construct and criterion approach according to COSMIN guidelines. Results: The MIC estimates of RMDQ, ODI and NRS scores varied between a 15–40% reduction, depending on including “slightly improved” in the definition of MIC or not. The MIC estimates for EQ5D were lower. The credibility of the estimates was moderate. For responsiveness, five out of six hypotheses were confirmed and AUC was >0.7 for all PROMs. Conclusion: When evaluated in a clinical trial of patients with chronic LBP and Modic changes, MIC thresholds for all PROMs were on the lower spectrum of previous estimates, varying depending on the definition of MIC. Responsiveness was sufficient

Cost–utility analysis of antibiotic treatment in patients with chronic low back pain and Modic changes: results from a randomised, placebo-controlled trial in Norway (the AIM study)

Objective: To evaluate the cost–utility of 100 days of antibiotics in patients with chronic low back pain (LBP) and type I or II Modic changes included in the Antibiotic treatment In patients with chronic low back pain and Modic changes (AIM) study. Design: A cost–utility analysis from a societal and healthcare perspective alongside a double- blinded, parallel group, placebo, multicentre trial. Setting: Hospital outpatient clinics at six hospitals in Norway. The main results from the AIM study showed a small effect in back- related disability in favour of the antibiotics group, and slightly larger in those with type I Modic changes, but this effect was below the pre- defined threshold for clinically relevant effect. Participants: 180 patients with chronic LBP, previous disc herniation and Modic changes type I (n=118) or type II (n=62) were randomised to antibiotic treatment (n=89) or placebo- control (n=91). Interventions: Oral treatment with either 750 mg amoxicillin or placebo three times daily for 100 days. Main outcome measures: Quality- adjusted life years (QALYs) by EuroQoL- 5D over 12 months and costs for healthcare and productivity loss measured in Euro (€1=NOK 10), in the intention- to- treat population. Cost– utility was expressed in incremental cost- effectiveness ratio (ICER). Results: Mean (SD) total cost was €21 046 (20 105) in the amoxicillin group and €19 076 (19 356) in the placebo group, mean difference €1970 (95% CI; −3835 to 7774). Cost per QALY gained was €24 625. In those with type I Modic changes, the amoxicillin group had higher healthcare consumption than the placebo group, resulting in €39 425 per QALY gained. Given these ICERs and a willingness- to- pay threshold of €27 500 (NOK 275 000), the probability of amoxicillin being cost- effective was 51%. Even when the willingness- to- pay threshold increased to €55 000, the probability of amoxicillin being cost- effective was never higher than 53%. Conclusions: Amoxicillin treatment showed no evidence of being cost- effective for people with chronic LBP and Modic changes during 1- year follow- up

Macrophage migration inhibitory factor: A potential biomarker for chronic low back pain in patients with Modic changes

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

Minimal important change was on the lower spectrum of previous estimates and responsiveness was sufficient for core outcomes in chronic low back pain

Objectives The objective of this study was to estimate the minimal important change (MIC) and responsiveness of core patient reported outcome measures for chronic low back pain (LBP) and Modic changes. Study Design and Setting In the Antibiotics in Modic changes (AIM) trial we measured disability (RMDQ, ODI), LBP intensity (NRS) and health-related quality of life (EQ5D) electronically at baseline, three- and 12-month follow-up. MICs were estimated using Receiver Operating Curve (ROC) curve and Predictive modeling analyses against the global perceived effect. Credibility of the estimates was assessed by a standardized set of criteria. Responsiveness was assessed by a construct and criterion approach according to COSMIN guidelines. Results The MIC estimates of RMDQ, ODI and NRS scores varied between a 15–40% reduction, depending on including “slightly improved” in the definition of MIC or not. The MIC estimates for EQ5D were lower. The credibility of the estimates was moderate. For responsiveness, five out of six hypotheses were confirmed and AUC was >0.7 for all PROMs. Conclusion When evaluated in a clinical trial of patients with chronic LBP and Modic changes, MIC thresholds for all PROMs were on the lower spectrum of previous estimates, varying depending on the definition of MIC. Responsiveness was sufficient