ISSLS PRIZE IN CLINICAL SCIENCE 2018: longitudinal analysis of inflammatory, psychological, and sleep-related factors following an acute low back pain episode—the good, the bad, and the ugly
Prospective longitudinal study.
To determine whether systemic cytokines and C-reactive protein (CRP) during an acute episode of low back pain (LBP) differ between individuals who did and did not recover by 6 months and to identify sub-groups based on patterns of inflammatory, psychological, and sleep features associated with recovery/non-recovery.
Summary of background data
Systemic inflammation is observed in chronic LBP and may contribute to the transition from acute to persistent LBP. Longitudinal studies are required to determine whether changes present early or develop over time. Psychological and/or sleep-related factors may be related.
Individuals within 2 weeks of onset of acute LBP (N = 109) and pain-free controls (N = 55) provided blood for assessment of CRP, tumor necrosis factor (TNF), interleukin-6 (IL-6) and interleukin-1β, and completed questionnaires related to pain, disability, sleep, and psychological status. LBP participants repeated measurements at 6 months. Biomarkers were compared between LBP and control participants at baseline, and in longitudinal (baseline/6 months) analysis, between unrecovered (≥pain and disability), partially recovered (reduced pain and/or disability) and recovered (no pain and disability) participants at 6 months. We assessed baseline patterns of inflammatory, psychological, sleep, and pain data using hierarchical clustering and related the clusters to recovery (% change in pain) at 6 months.
CRP was higher in acute LBP than controls at baseline. In LBP, baseline CRP was higher in the recovered than non-recovered groups. Conversely, TNF was higher at both time-points in the non-recovered than recovered groups. Two sub-groups were identified that associated with more (“inflammatory/poor sleep”) or less (“high TNF/depression”) recovery.
This is the first evidence of a relationship between an “acute-phase” systemic inflammatory response and recovery at 6 months. High inflammation (CRP/IL-6) was associated with good recovery, but specific elevation of TNF, along with depressive symptoms, was associated with bad recovery. Depression and TNF may have a two-way relationship.
KeywordsPro-inflammatory cytokines C-reactive protein (CRP) Tumor necrosis factor (TNF) Interleukin-6 (IL-6) Interleukin-1β (IL-1β) Systemic Depression Sleep Low back pain (LBP) Longitudinal Transition to chronicity
This research was funded by the National Health and Medical Research Council (NHMRC) of Australia (Program Grant: ID631717; Project Grant ID631369). PWH supported by NHMRC Fellowship ID1002190. The manuscript submitted does not contain information about medical device(s)/drug(s).
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest related to this work.
Approved by The University of Queensland Institutional Medical Research Ethics Committee.
- 7.Shimura Y, Kurosawa H, Sugawara Y, Tsuchiya M, Sawa M, Kaneko H, Futami I, Liu L, Sadatsuki R, Hada S, Iwase Y, Kaneko K, Ishijima M (2013) The factors associated with pain severity in patients with knee osteoarthritis vary according to the radiographic disease severity: a cross-sectional study. Osteoarthr Cartilage 21(9):1179–1184CrossRefGoogle Scholar
- 9.Moshage HJ, Roelofs HMJ, Vanpelt JF, Hazenberg BPC, Vanleeuwen MA, Limburg PC, Aarden LA, Yap SH (1988) The effect of interleukin-1, interleukin-6 and its interrelationship on the synthesis of serum amyloid a-reactive and C-reactive protein in primary cultures of adult human hepatocytes. Biochem Bioph Res Co 155(1):112–117CrossRefGoogle Scholar
- 10.Anty R, Bekri S, Luciani N, Saint-Paul MC, Dahman M, Iannelli A, Ben Amor I, Staccini-Myx A, Huet PM, Gugenheim J, Sadoul JL, Le Marchand-Brustel Y, Tran A, Gual P (2006) The inflammatory C-reactive protein is increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome, type 2 diabetes, and NASH. Am J Gastroenterol 101(8):1824–1833PubMedCrossRefGoogle Scholar
- 19.Henschke N, Maher CG, Refshauge KM, Herbert RD, Cumming RG, Bleasel J, York J, Das A, McAuley JH (2008) Prognosis in patients with recent onset low back pain in Australian primary care: inception cohort study. Br Med J 337(7662):154–157Google Scholar
- 31.Mallen CD, Peat G, Thomas E, Dunn KM, Croft PR (2007) Prognostic factors for musculoskeletal pain in primary care: a systematic review. Brit J Gen Pract 57(541):655–661Google Scholar
- 43.Thiele JR, Zeller J, Bannasch H, Stark GB, Peter K, Eisenhardt SU (2015) Targeting C-reactive protein in inflammatory disease by preventing conformational changes. Mediators Inflamm 2015. https://doi.org/10.1155/2015/372432
- 44.Braig D, Nero TL, Koch HG, Kaiser B, Wang X, Thiele JR, Morton CJ, Zeller J, Kiefer J, Potempa LA, Mellett NA, Miles LA, Du XJ, Meikle PJ, Huber-Lang M, Stark GB, Parker MW, Peter K, Eisenhardt SU (2017) Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites. Nat Commun 8:14188PubMedPubMedCentralCrossRefGoogle Scholar
- 46.Pritchett JW (1996) C-reactive protein levels determine the severity of soft-tissue injuries. Am J Orthop (Belle Mead NJ) 25(11):759–761Google Scholar
- 55.Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S, Mahieu P, Malaise M, De Groote D, Louis R, Belaiche J (1998) Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 113(3):401–406PubMedPubMedCentralCrossRefGoogle Scholar
- 64.Boettger MK, Weber K, Grossmann D, Gajda M, Bauer R, Bar KJ, Schulz S, Voss A, Geis C, Brauer R, Schaible HG (2010) Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation. Arthritis Rheum 62(5):1308–1318PubMedCrossRefGoogle Scholar
- 68.Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Sergeeva M, Saake M, Garcia M, Kollias G, Straub RH, Sporns O, Doerfler A, Brune K, Schett G (2011) Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci USA 108(9):3731–3736PubMedPubMedCentralCrossRefGoogle Scholar
- 82.Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. BBA-Mol Cell Res 1813(5):878–888Google Scholar
- 99.Hurtado-Alvarado G, Pavon L, Castillo-Garcia SA, Hernandez ME, Dominguez-Salazar E, Velazquez-Moctezuma J, Gomez-Gonzalez B (2013) Sleep loss as a factor to induce cellular and molecular inflammatory variations. Clin Dev Immunol 2013:801341. https://doi.org/10.1155/2013/801341 PubMedPubMedCentralCrossRefGoogle Scholar
- 111.McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, Goldfarb RH, Kitson RP, Miller AH, Spencer RL, Weiss JM (1997) The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Rev 23(1–2):79–133PubMedCrossRefGoogle Scholar
- 114.Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S (2006) Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63(11):1209–1216PubMedCrossRefGoogle Scholar
- 118.Martuscello RT, Spengler RN, Bonoiu AC, Davidson BA, Helinski J, Ding H, Mahajan S, Kumar R, Bergey EJ, Knight PR, Prasad PN, Ignatowski TA (2012) Increasing TNF levels solely in the rat hippocampus produces persistent pain-like symptoms. Pain 153(9):1871–1882PubMedPubMedCentralCrossRefGoogle Scholar
- 124.Kemp DE, Ganocy SJ, Brecher M, Carlson BX, Edwards S, Eudicone JM, Evoniuk G, Jansen W, Leon AC, Minkwitz M, Pikalov A, Stassen HH, Szegedi A, Tohen M, Van Willigenburg AP, Calabrese JR (2011) Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression. J Affect Disord 130(1–2):171–179PubMedCrossRefGoogle Scholar