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

Lars Christian Haugli Bråten,1 Elisabeth Gjefsen,1,2 Kristina Gervin,1 Are Hugo Pripp,3 Jan Sture Skouen,4 Elina Schistad,5 Linda Margareth Pedersen,1 Monica Wigemyr,1 Kaja Kristine Selmer,1 Hans Christian Dalsbotten Aass,6 Guro Goll,7 Jens Ivar Brox,5 Ansgar Espeland,8,9 Lars Grøvle,10 John-Anker Zwart,1,2 Kjersti Storheim1,11 On behalf of The AIM-study group1Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital HF, Oslo, Norway; 2Faculty of Medicine, University of Oslo, Oslo, Norway; 3Oslo Centre of Biostatistics and Epidemiology Research Support Services, Oslo University Hospital Ulleval, Oslo, Norway; 4Department of Physical Medicine and Rehabilitation, Haukeland University Hospital, Bergen, Norway; 5Department of Physical Medicine and Rehabilitation, Oslo University Hospital HF, Oslo, Norway; 6Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; 7Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway; 8Department of Radiology, Haukeland University Hospital, Bergen, Norway; 9Department of Clinical Medicine, University of Bergen, Bergen, Norway; 10Department of Rheumatology, Østfold Hospital Trust, Grålum, Norway; 11Oslo Metropolitan University, Department of Physiotherapy, Oslo, NorwayCorrespondence: Lars Christian Haugli Bråten, Tel +4722117769, Email l.c.h.braten@studmed.uio.noObjective: 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