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

References

• Modic MT, Steinberg PM, Ross JS, Masaryk TJ, Carter JR. Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging. Radiology. 1988;166(1 Pt 1):193. doi:10.1148/radiology.166.1.3336678
   PubMed Web of Science ®Google Scholar
• Dudli S, Liebenberg E, Magnitsky S, Lu B, Lauricella M, Lotz JC. Modic type 1 change is an autoimmune response that requires a proinflammatory milieu provided by the “Modic disc”. Spine J. 2018;18(5):831–844. doi:10.1016/j.spinee.2017.12.004
   PubMed Web of Science ®Google Scholar
• Bobechko W, Hirsch C. Auto-immune response to nucleus pulposus in the rabbit. J Bone Joint Surg Br. 1965;47(3):574–580. doi:10.1302/0301-620X.47B3.574
   PubMedGoogle Scholar
• Geiss A, Larsson K, Junevik K, Rydevik B, Olmarker K. Autologous nucleus pulposus primes T cells to develop into interleukin‐4‐producing effector cells: an experimental study on the autoimmune properties of nucleus pulposus. J Orthopaed Res. 2009;27(1):97–103. doi:10.1002/jor.20691
   PubMed Web of Science ®Google Scholar
• Gertzbein S, Tait J, Devlin S. The stimulation of lymphocytes by nucleus pulposus in patients with degenerative disk disease of the lumbar spine. Clin Orthop Relat Res. 1977;123:149–154.
   Google Scholar
• Capoor MN, Konieczna A, McDowell A, et al. Pro-inflammatory and neurotrophic factor responses of cells derived from degenerative human intervertebral discs to the opportunistic pathogen Cutibacterium acnes. Int J Mol Sci. 2021;22(5):2347. doi:10.3390/ijms22052347
   PubMed Web of Science ®Google Scholar
• Adams MA, Freeman BJ, Morrison HP, Nelson IW, Dolan P. Mechanical initiation of intervertebral disc degeneration. Spine. 2000;25(13):1625–1636. doi:10.1097/00007632-200007010-00005
   PubMed Web of Science ®Google Scholar
• Capoor M, Ruzicka F, Machackova T, et al. Prevalence of propionibacterium acnes in intervertebral discs of patients undergoing lumbar microdiscectomy: a prospective cross-sectional study. PLoS One. 2016;11(8):e0161676. doi:10.1371/journal.pone.0161676
   PubMed Web of Science ®Google Scholar
• Capoor MN, Ruzicka F, Schmitz JE, et al. Propionibacterium acnes biofilm is present in intervertebral discs of patients undergoing microdiscectomy. PLoS One. 2017;12(4):e0174518. doi:10.1371/journal.pone.0174518
   PubMed Web of Science ®Google Scholar
• Chen Z, Zheng Y, Yuan Y, et al. Modic changes and disc degeneration caused by inoculation of Propionibacterium acnes inside intervertebral discs of rabbits: a pilot study. Biomed Res Int. 2016;2016:9612437. doi:10.1155/2016/9612437
   PubMed Web of Science ®Google Scholar
• Dudli S, Liebenberg E, Magnitsky S, Miller S, Demir-Deviren S, Lotz JC. Propionibacterium acnes infected intervertebral discs cause vertebral bone marrow lesions consistent with Modic changes. J Orthopaed Res. 2016;34:1447–1455. doi:10.1002/jor.23265
   PubMed Web of Science ®Google Scholar
• Rajasekaran S, Tangavel C, Aiyer SN, et al. Is infection the possible initiator of disc disease? An insight from proteomic analysis. Eur Spine J. 2017;26:1384–1400. doi:10.1007/s00586-017-4972-3
   PubMed Web of Science ®Google Scholar
• Urquhart DM, Zheng Y, Cheng AC, et al. Could low grade bacterial infection contribute to low back pain? A systematic review. BMC Med. 2015;13:13. doi:10.1186/s12916-015-0267-x
   PubMed Web of Science ®Google Scholar
• Li B, Dong Z, Wu Y, et al. Association between lumbar disc degeneration and Propionibacterium acnes infection: clinical research and preliminary exploration of animal experiment. Spine. 2016;41(13):E764. doi:10.1097/BRS.0000000000001383
   PubMed Web of Science ®Google Scholar
• Benoist M. The Michel Benoist and Robert Mulholland yearly European Spine Journal review: a survey of the “medical” articles in the European Spine Journal, 2018. Eur Spine J. 2019;28(1):10–20. doi:10.1007/s00586-018-5857-9
   PubMed Web of Science ®Google Scholar
• Capoor MN, Birkenmaier C, Wang JC, et al. A review of microscopy-based evidence for the association of Propionibacterium acnes biofilms in degenerative disc disease and other diseased human tissue. Eur Spine J. 2019;28(12):2951–2971. doi:10.1007/s00586-019-06086-y
   PubMed Web of Science ®Google Scholar
• Albert HB, Sorensen JS, Christensen BS, Manniche C. Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. Eur Spine J. 2013;22(4):697–707.
   PubMed Web of Science ®Google Scholar
• Bråten LCH, Rolfsen MP, Espeland A, et al. Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial. BMJ. 2019;367:l5654. doi:10.1136/bmj.l5654
   PubMedGoogle Scholar
• Bråten LCH, Grøvle L, Espeland A, et al. Clinical effect modifiers of antibiotic treatment in patients with chronic low back pain and Modic changes-secondary analyses of a randomised, placebo-controlled trial (the AIM study). BMC Musculoskelet Disord. 2020;21(1):1–11. doi:10.1186/s12891-020-03422-y
   Web of Science ®Google Scholar
• Kristoffersen PM, Bråten LC, Vetti N, et al. Oedema on STIR modified the effect of amoxicillin as treatment for chronic low back pain with Modic changes—subgroup analysis of a randomized trial. Eur Radiol. 2021;31(6):4285–4297. doi:10.1007/s00330-020-07542-w
   PubMed Web of Science ®Google Scholar
• Heggli I, Schüpbach R, Herger N, et al. OP0083 Infectious and Autoinflammatory Modic Type 1 Changes Have Different Pathomechanisms. BMJ Publishing Group Ltd; 2021.
   Google Scholar
• Schirmer M, Kumar V, Netea MG, Xavier RJ. The causes and consequences of variation in human cytokine production in health. Curr Opin Immunol. 2018;54:50–58. doi:10.1016/j.coi.2018.05.012
   PubMed Web of Science ®Google Scholar
• Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10(1):44–56. doi:10.1038/nrrheum.2013.160
   PubMed Web of Science ®Google Scholar
• Dudli S, Fields AJ, Samartzis D, Karppinen J, Lotz JC. Pathobiology of Modic changes. Eur Spine J. 2016;25(11):3723–3734. doi:10.1007/s00586-016-4459-7
   PubMed Web of Science ®Google Scholar
• Dudli S, Miller S, Demir-Deviren S, Lotz JC. Inflammatory response of disc cells against Propionibacterium acnes depends on the presence of lumbar Modic changes. Eur Spine J. 2018;27(5):1013–1020. doi:10.1007/s00586-017-5291-4
   PubMed Web of Science ®Google Scholar
• Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochimica et Biophysica Acta (BBA). 2014;1843(11):2563–2582.
   PubMed Web of Science ®Google Scholar
• Gjefsen E, Gervin K, Goll G, et al. Macrophage migration inhibitory factor: a potential biomarker for chronic low back pain in patients with Modic changes. RMD Open. 2021;7(2):e001726. doi:10.1136/rmdopen-2021-001726
   PubMed Web of Science ®Google Scholar
• Altan-Bonnet G, Mukherjee R. Cytokine-mediated communication: a quantitative appraisal of immune complexity. Nat Rev Immunol. 2019;19(4):205–217. doi:10.1038/s41577-019-0131-x
   PubMed Web of Science ®Google Scholar
• Kothur K, Wienholt L, Mohammad SS, et al. Utility of CSF cytokine/chemokines as markers of active intrathecal inflammation: comparison of demyelinating, anti-NMDAR and enteroviral encephalitis. PLoS One. 2016;11(8):e0161656. doi:10.1371/journal.pone.0161656
   PubMed Web of Science ®Google Scholar
• Michael BD, Griffiths MJ, Granerod J, et al. Characteristic cytokine and chemokine profiles in encephalitis of infectious, immune-mediated, and unknown aetiology. PLoS One. 2016;11(1):e0146288. doi:10.1371/journal.pone.0146288
   PubMed Web of Science ®Google Scholar
• Kothur K, Bandodkar S, Wienholt L, et al. Etiology is the key determinant of neuroinflammation in epilepsy: elevation of cerebrospinal fluid cytokines and chemokines in febrile infection‐related epilepsy syndrome and febrile status epilepticus. Epilepsia. 2019;60(8):1678–1688. doi:10.1111/epi.16275
   PubMed Web of Science ®Google Scholar
• Kyogoku C, Smiljanovic B, Grün JR, et al. Cell-specific type I IFN signatures in autoimmunity and viral infection: what makes the difference? PLoS One. 2013;8(12):e83776. doi:10.1371/journal.pone.0083776
   PubMed Web of Science ®Google Scholar
• Yeung W-CG, Al-Shabeeb A, Pang CNI, et al. Children with islet autoimmunity and enterovirus infection demonstrate a distinct cytokine profile. Diabetes. 2012;61(6):1500–1508. doi:10.2337/db11-0264
   PubMed Web of Science ®Google Scholar
• Brinkmann J, Zeißler E-C, Scharrenberg JS, et al. The diagnostic value of cytokines for the discrimination of vertebral osteomyelitis and degenerative diseases of the spine. Cytokine. 2022;150:155782. doi:10.1016/j.cyto.2021.155782
   PubMed Web of Science ®Google Scholar
• Yu Y, Champer J, Agak GW, Kao S, Modlin RL, Kim J. Different Propionibacterium acnes phylotypes induce distinct immune responses and express unique surface and secreted proteomes. J Investig Dermatol. 2016;136(11):2221–2228. doi:10.1016/j.jid.2016.06.615
   PubMed Web of Science ®Google Scholar
• Yuan Y, Chen Y, Zhou Z, et al. Association between chronic inflammation and latent infection of Propionibacterium acnes in non-pyogenic degenerated intervertebral discs: a pilot study. Eur Spine J. 2018;27(10):2506–2517. doi:10.1007/s00586-017-5363-5
   PubMed Web of Science ®Google Scholar
• Jiao Y, Yuan Y, Lin Y, et al. Propionibacterium acnes induces discogenic low back pain via stimulating nucleus pulposus cells to secrete pro-algesic factor of IL-8/CINC-1 through TLR2–NF-κB p65 pathway. J Mol Med. 2019;97(1):25–35. doi:10.1007/s00109-018-1712-z
   PubMed Web of Science ®Google Scholar
• Schmid B, Hausmann O, Hitzl W, Achermann Y, Wuertz-Kozak K. The role of Cutibacterium acnes in intervertebral disc inflammation. Biomedicines. 2020;8(7):186. doi:10.3390/biomedicines8070186
   PubMed Web of Science ®Google Scholar
• Romics JL, Dolganiuc A, Velayudham A, et al. Toll‐like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni‐bacterium acnes. J Leukoc Biol. 2005;78(6):1255–1264. doi:10.1189/jlb.0804448
   PubMed Web of Science ®Google Scholar
• Basal E, Jain A, Kaushal G. Antibody response to crude cell lysate of propionibacterium acnes and induction of pro-inflammatory cytokines in patients with acne and normal healthy subjects. J Microbiol. 2004;42(2):117–125.
   PubMed Web of Science ®Google Scholar
• Di Cesare PE, Chang E, Preston CF, Liu C-J. Serum interleukin-6 as a marker of periprosthetic infection following total Hip and knee arthroplasty. JBJS. 2005;87(9):1921–1927. doi:10.2106/00004623-200509000-00003
   PubMedGoogle Scholar
• Ugge H, Carlsson J, Söderquist B, Fall K, Andén O, Davidsson S. The influence of prostatic Cutibacterium acnes infection on serum levels of IL6 and CXCL8 in prostate cancer patients. Infect Agent Cancer. 2018;13(1):34. doi:10.1186/s13027-018-0204-7
   PubMedGoogle Scholar
• Bråten LC, Gervin K, Pripp AH, et al. Statistical analysis plan for analysis of cytokines as prognostic factors and predictors of antibiotic treatment effect in the AIM trial. 2021.
   Google Scholar
• Grotle M, Vøllestad M, Brox M. Cross-cultural adaptation of the Norwegian versions of the Roland-Morris Disability Questionnaire and the Oswestry Disability Index. J Rehabil Med. 2003;35(5):241–247. doi:10.1080/16501970306094
   PubMed Web of Science ®Google Scholar
• Chiarotto A, Boers M, Deyo RA, et al. A core outcome measurement set for low back pain clinical trials. Orthopaed Proc. 2018;100-B(SUPP_2):29.
   Google Scholar
• Fairbank JC, Pynsent PB. The Oswestry disability index. Spine. 2000;25(22):2940. doi:10.1097/00007632-200011150-00017
   PubMed Web of Science ®Google Scholar
• Dworkin HR, Turk CD, Farrar TJ, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(12):9–19. doi:10.1016/j.pain.2004.09.012
   PubMed Web of Science ®Google Scholar
• Hingorani AD, van der Windt DA, Riley RD, et al. Prognosis research strategy (PROGRESS) 4: stratified medicine research. BMJ. 2013;346:125.
   Google Scholar
• Lipkovich I, Dmitrienko A, D’Agostino B. Tutorial in biostatistics: data‐driven subgroup identification and analysis in clinical trials. Stat Med. 2017;36(1):136–196. doi:10.1002/sim.7064
   PubMed Web of Science ®Google Scholar
• Hiyama A, Suyama K, Sakai D, Tanaka M, Watanabe M. Correlational analysis of chemokine and inflammatory cytokine expression in the intervertebral disc and blood in patients with lumbar disc disease. J Orthopaed Res. 2022;40(5):1213–1222. doi:10.1002/jor.25136
   PubMed Web of Science ®Google Scholar
• Boisson M, Borderie D, Henrotin Y, et al. Serum biomarkers in people with chronic low back pain and Modic 1 changes: a case-control study. Sci Rep. 2019;9(1):1–5. doi:10.1038/s41598-019-46508-x
   PubMedGoogle Scholar
• Gilligan CJ, Cohen SP, Fischetti VA, Hirsch JA, Czaplewski LG. Chronic Low Back Pain, bacterial infection and treatment with antibiotics. Spine J. 2021;21:903–914. doi:10.1016/j.spinee.2021.02.013
   PubMed Web of Science ®Google Scholar
• Ohrt‐Nissen S, Fritz BG, Walbom J, et al. Bacterial biofilms: a possible mechanism for chronic infection in patients with lumbar disc herniation–a prospective proof‐of‐concept study using fluorescence in situ hybridization. Apmis. 2018;126(5):440–447. doi:10.1111/apm.12841
   PubMed Web of Science ®Google Scholar
• Lingsma H, Roozenbeek B, Steyerberg E. Covariate adjustment increases statistical power in randomized controlled trials. J Clin Epidemiol. 2010;63(12):1391. doi:10.1016/j.jclinepi.2010.05.003
   PubMed Web of Science ®Google Scholar
• Vanelderen P, Van Zundert J, Kozicz T, et al. Effect of minocycline on lumbar radicular neuropathic pain: a randomized, placebo-controlled, double-blind clinical trial with amitriptyline as a comparator. Anesthesiology. 2015;122(2):399–406. doi:10.1097/ALN.0000000000000508
   PubMed Web of Science ®Google Scholar
• McNamara AL, Dickerson EC, Gomez-Hassan DM, Cinti SK, Srinivasan A. Yield of image-guided needle biopsy for infectious discitis: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2017;38(10):2021–2027. doi:10.3174/ajnr.A5337
   PubMed Web of Science ®Google Scholar