Please cite this article as: Klyne, D.M., Barbe, M.F., Hodges, P.W., Systemic inflammatory profiles and their relationships with demographic, behavioural and clinical features in acute low back pain, Brain, Behavior, and Immunity (2016), doi: http://dx.doi.org/10. 1016/j.bbi.2016.10.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. and control participants, and in a separate analysis, for those with "high-pain" (VAS≥4) and "low-pain" (VAS<4). The relationships between biomarkers and all other variables, including other cytokines/CRP were assessed. CRP was higher in LBP than controls and in those with high-than low-pain (p<0.01). IL-6 was higher in those with high-than low-pain (p<0.05), but not controls. Various pain and non-pain factors were associated with each biomarker differently. These findings suggest systemic CRP and IL-6 are important contributors to inflammation in the early post-onset phase of LBP and that various factors can shape these responses.3

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. These slides can be retrieved under Electronic Supplementary Material.

Sensory changes indicative of increased/decreased central processing of pain and nociceptive input presented differently between individuals with acute LBP and were related to factors such as sleep and alcohol. This may underlie variation in outcome and suggest potential for early identification of individuals with poor long-term outcome.

Purpose: Chronic low back pain causes structural remodelling and inflammation in the multifidus muscle. Collagen expression is increased in the multifidus of humans with lumbar disc degeneration.However, the extent and mechanisms underlying the increased fibrotic activity in the multifidus are unknown. Physical activity reduces local inflammation that precedes multifidus fibrosis during intervertebral disc degeneration (IDD) buts is effect on amelioration of fibrosis is unknown. This study aimed to assess development of fibrosis and its underlying genetic network during IDD and the impact of physical activity.Methods: Wildtype and SPARC-null mice were either sedentary or housed with a running wheel, to allow voluntary physical activity. At 12 months of age, IDD was assessed with MRI and multifidus muscle samples were harvested from L2-L6. In SPARC-null mice, the L1/2 and L3/4 discs had low and high levels of IDD, respectively. Thus, multifidus samples from L2 and L4 were allocated to low and high-IDD groups compared to assess the effects of IDD and physical activity on connective tissue and fibrotic genes.Results: High-IDD was associated with greater connective tissue thickness and dysregulation of Collagen-III, Fibronectin, CTGF, Substance P, TIMP1 and TIMP2 in the multifidus muscle. Physical activity attenuated the IDD-dependent increased connective tissue thickness and reduced the expression of Collagen-1, Fibronectin, CTGF, Substance P, MMP2 and TIMP2 in SPARC-null animals and wildtype mice. Collagen-III and TIMP1 were only reduced in wildtype animals.Conclusions: These data reveal the fibrotic networks that promote fibrosis in the multifidus muscle during chronic IDD. Furthermore, physical activity is shown to reduce fibrosis and regulate the fibrotic gene network.

This study indicates that pressure pain threshold as the test stimulus provides a more valid measure of pain-induced CPM than pain response to a suprathreshold heat stimulus. Induction and magnitude of CPM is independent of stimuli arrangement, as long as ipsilateral homotopic sites are avoided. These findings clarify methods to study CPM.

Encapsulation of median nerves is a hallmark of overuse-induced median mononeuropathy and contributes to functional declines. We tested if an antibody against CTGF/CCN2 (termed FG-3019 or Pamrevlumab) reduces established neural fibrosis and sensorimotor declines in a clinically relevant rodent model of overuse in which median mononeuropathy develops. Young adult female rats performed a high repetition high force (HRHF) lever-pulling task for 18 weeks. Rats were then euthanised at 18 weeks (HRHF untreated), or rested and systemically treated for 6 weeks with either an anti-CCN2 monoclonal antibody (HRHF-Rest/FG-3019) or IgG (HRHF-Rest/IgG), with results compared with nontask control rats. Neuropathology was evident in HRHF-untreated and HRHF-Rest/IgG rats as increased perineural collagen deposition and degraded myelin basic protein (dMBP) in median nerves, and increased substance P in lower cervical dorsal root ganglia (DRG), compared with controls. Both groups showed functional declines, specifically, decreased sensory conduction velocity in median nerves, noxious cold temperature hypersensitivity, and grip strength declines, compared with controls. There were also increases of ATF3-immunopositive nuclei in ventral horn neurons in HRHFuntreated rats, compared with controls (which showed none). FG-3019-treated rats showed no increase above control levels of perineural collagen or dMBP in median nerves, Substance P in lower cervical DRGs, or ATF3-immunopositive nuclei in ventral horns, and similar median nerve conduction velocities and thermal sensitivity, compared with controls. We hypothesize that neural fibrotic processes underpin the sensorimotor declines by compressing or impeding median nerves during movement, and that inhibiting fibrosis using an anti-CCN2 treatment reverses these effects.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights  Central sensitisation presents in some but not all individuals with acute back pain  Presence of central sensitisation early does not necessarily precede poor outcome  Early sensitisation precedes poor outcome when combined with psychological factors

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