Cytokine Patterns as Predictors of Antibiotic Treatment Effect in Chronic Low Back Pain with Modic Changes: Subgroup Analyses of a Randomized Trial (AIM Study)

Abstract

Objective

Randomized trials testing the effect of antibiotics for chronic low back pain (LBP) with vertebral bone marrow changes on MRI (Modic changes) report inconsistent results. A proposed explanation is subgroups with low grade discitis where antibiotics are effective, but there is currently no method to identify such subgroups. The objective of the present study was to evaluate whether distinct patterns of serum cytokine levels predict any treatment effect of oral amoxicillin at one-year follow-up in patients with chronic low back pain and Modic changes at the level of a previous lumbar disc herniation.

Design

We used data from an overpowered, randomized, placebo-controlled trial (the AIM study) that tested 100 days of oral 750 mg amoxicillin vs placebo three times daily in hospital outpatients with chronic (>6 months) LBP with pain intensity ≥5 on a 0–10 numerical rating scale and Modic changes type 1 (oedema type) or 2 (fatty type). We measured serum levels of 40 inflammatory cytokines at baseline and analysed six predefined potential predictors of treatment effect based on cytokine patterns in 78 randomized patients; three analyses with recursive partitioning, one based on cluster analysis and two based on principal component analyses. The primary outcome was the Roland–Morris Disability Questionnaire score at one-year follow-up in the intention to treat population. The methodology and overall results of the AIM study were published previously.

Results

The 78 patients were 25–62 years old and 47 (60%) were women. None of the three recursive partitioning analyses resulted in any suggested subgroups. Of all main analyses, the largest effect estimate (mean difference between antibiotic and placebo groups) was seen in a subgroup not predefined as of main interest (Cluster category 3+4; −2.0, 95% CI: −5.2–1.3, RMDQ points; p-value for interaction 0.54).

Conclusion

Patterns of inflammatory serum cytokine levels did not predict treatment effect of amoxicillin in patients with chronic LBP and Modic changes.

Clinical Trial Registration Number

ClinicalTrials.gov (identifier: NCT02323412).

Keywords:

• low back pain
• Modic changes
• infection
• cytokines
• inflammation

Data Sharing Statement

Requests to access data should be addressed to [email protected]. De-identified individual participant data (including data dictionary) will be available to medical researchers on request in accordance with local registration and ethical approval when the article is published until 1 July 2029. All proposals requesting data access will need to specify an analysis plan and will need approval of the scientific board before any data can be released.

Acknowledgments

The AIM study group: University Hospital North Norway, Tromsø (two patients): Terese Fors, Guro Kjos, Ida Beate Østhus (Department of Rehabilitation). Trondheim University Hospital, Trondheim (11 patients): Gunn Hege Marchand, Britt Elin Lurud, Fredrik Granvigen (Department of Physical Medicine and Rehabilitation), Hege Andersen (National Advisory Unit of Spinal Surgery), Øystein Petter Nygaard, Vidar Rao (Department of Neurosurgery). Haukeland University Hospital, Bergen (14 patients): Thomas Istvan Kadar and Siv Krüger Claussen (Department of Physical Medicine and Rehabilitation), Erling Andersen (Department of Clinical Engineering), Per Kristoffersen and Nils Vetti (Department of Radiology), Jörg Aßmus (Centre for Clinical Research). Vestre Viken Hospital, Drammen (16 patients): Sigrun Randen (Department of Physical Medicine and Rehabilitation), Hilde Presberg (Department of Neurology). Oslo University Hospital, Oslo (20 patients): Linda Margareth Pedersen, Bendik Slagsvold Winsvold (FORMI), Karianne Wiger Gammelsrud (Department of microbiology), Maria Dehli Vigeland, Benedicte Alexandra Lie, Siri Tennebø Flåm, Magnus Dehli Vigeland (Department of Medical Genetics). Østfold Hospital Trust (15 patients): Marianne Thorsø, Knut Morten Huneide, (Department of Physical Medicine and Rehabilitation), Veronica Sørensen (Department of Rheumatology). Thor Einar Holmgard (patient representative). We thank Helse Sør-Øst (grant no: 2015090) and Helse Vest (grant no: 911938 and 911891) for funding the AIM study, KLINBEFORSK (grant no: 2017201) and all patients participating in this study.

Author Contributions

KG Analysis and interpretation of the data; AHP Interpretation and statistical expertise; ES and LMP Conception and design of study and acquisition of data; MW Acquisition of data, administrative, technical, and logistic support; HCA Acquisition of data and conception and design of study; EF, JSS, KKS, GLG, JIB, AE, JAZ, KS and LG Conception and design of study; JAZ, AE and KS Obtaining funding; LCHB Drafting of article and analysis and interpretation of data. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

Dr Lars Christian Haugli Bråten reports grants from Helse Sør-Øst, grants from KLINBEFORSK, during the conduct of the study. Dr Kaja Kristine Selmer reports grants from Norwegian Research Council, during the conduct of the study; personal fees from Roche, meeting sponsorship to institution (Oslo University Hospital) from Eisai AB, personal fees from OrionPharma, grants from Norwegian Research Council, grants from DAM foundation, grants from Novo Nordic Foundation, grants from NordForsk, grants from The National Advisory Unit on Rare Disorders in Norway, outside the submitted work. Dr Guro Goll reports personal fees from AbbVie, personal fees from Novartis, outside the submitted work. Prof. Dr. Ansgar Espeland reports grants from Helse Vest, during the conduct of the study. The authors report no conflicts of interest in this work.

Additional information

Funding

Funding was granted by governmental organisations Helse Sør-Øst (grant No 2015090), Helse Vest (grant No 911938 and 911891) and KLINBEFORSK (grant no: 2017201), which had no part in the planning, performing, or reporting of the trial.