Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure

Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.

Determining factors related to impaired spinal and hip mobility in patients with axial spondyloarthritis: longitudinal results from the DESIR cohort

ObjectiveTo investigate the determinants of impaired spinal and hip mobility in patients with early axial spondyloarthritis (axSpA).MethodsFive-year longitudinal data from the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort were analysed. Associations were investigated using generalised estimating equations, using Bath Ankylosing Spondylitis Metrology Index (BASMI) linear or each of the five components of BASMI as dependent variables, and clinical and demographic variables as independent variables in univariable models. Multivariable analyses were performed, adjusting for potential confounders.ResultsData from 644 patients and 5152 visits were analysed. Higher BASMI values were independently and positively associated with Ankylosing Spondylitis Disease Activity Score C reactive protein (ASDAS-CRP) (adjusted B (adjB)=0.21; 95% CI=0.15 to 0.28), MRI spinal inflammation score (adjB=0.11; 95% CI=0.04 to 0.19), enthesitis score (adjB=0.02; 95% CI=0.01 to 0.04) and age (adjB=0.02; 95% CI=0.01 to 0.03). All BASMI components were independently associated with ASDAS-CRP and MRI spinal inflammation, except for maximal intermalleolar distance (reflecting hip mobility), which was not associated with MRI spinal inflammation.ConclusionIn early axSpA, spinal mobility impairment is independently determined by clinical disease activity, MRI spinal inflammation, enthesitis and age. The influence of spinal inflammation prevails in early axSpA, as opposed to spinal structural damage, which may become more relevant in later disease stages.

Magnetic resonance imaging evaluation of posterior spinal tuberculosis: a cross-sectional study

Background Isolated posterior spinal (element) tuberculosis (TB) is uncommon compared to classical anterior spinal or para-discal TB. Here, we report magnetic resonance imaging (MRI) findings of posterior spinal TB in 19 patients without involvement of the vertebral body and intervertebral disc. Purpose To evaluate the MRI findings in isolated posterior spinal (element) TB. Material and Methods Clinical and MRI data of 19 patients of isolated posterior spinal TB were retrospectively evaluated. Results Of the 19 patients, group A comprised 4 (21%) patients with rapid onset lower limb weakness and pyramidal signs while group B comprised 15 (79%) patients without any neurological deficit. Lumbar vertebrae commonly affected 9 (47.4%) patients followed by dorsal vertebrae in 8 (42.1%) patients and cervical vertebrae in 2 (10.5%) patients. The pedicle was most commonly involved in 12 (63.2%) patients followed by the lamina in 11 (58%) patients, and spinous process and facet joint in 6 (31.6%) patients each. Extra-spinal inflammation/pyomyositis/paraspinal abscess was found in 13 (68.4%) patients followed by epidural abscess 3 (15.8%) patients and both extra spinal inflammation and epidural abscess in 3 (15.8%) patients (15.8%). Compressive cord myelopathy was observed in 4 (21%) patients, where three patients underwent emergency decompression laminectomy and the remaining 16 patients were treated conservatively with anti-tubercular therapy. Conclusion Initial diagnosis of isolated posterior element TB is challenging and requires a high index of suspicion. Early diagnosis of isolated posterior spinal TB is important as early treatment may be beneficial and decreases patient morbidity.

OP0076 CLINICAL DISEASE ACTIVITY, MRI SPINAL INFLAMMATION AND ENTHESITIS ARE KEY DETERMINANTS OF IMPAIRMENT OF SPINAL MOBILITY IN EARLY AXIAL SPONDYLOARTHRITIS – DATA FROM THE DESIR COHORT

Background:It has been shown that spinal mobility impairment in axial spondyloarthritis (axSpA) is independently determined both by irreversible spinal damage and by reversible spinal inflammation. However, these relationships have only been investigated in patients with longstanding disease (ankylosing spondylitis). Moreover, only the composite score Bath Ankylosing Spondylitis Metrology Index (BASMI) has been evaluated rather than individual mobility assessments.Objectives:Our aim was to investigate the determinants of spinal mobility in patients with early axSpA.Methods:We analysed longitudinal data from the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort, collected during the first five years of follow-up. We selected patients with a definite diagnosis of axSpA according to the treating rheumatologist, at the end of follow-up (month 60). Associations were tested using generalised estimating equations (GEE), a multilevel approach that adjusts for within-patient correlation. The Bath Ankylosing Spondylitis Metrology Index (BASMI) or the individual components of BASMI (lateral spinal flexion, tragus-to-wall distance, cervical rotation, anterior lumbar flexion, maximal intermalleolar distance) were used as dependent variables, and clinical and demographic variables were used as independent variables in univariable models. Spinal MRI inflammation was assessed using the Berlin scoring system and radiographic structural damage was assessed using the modified Stoke ankylosing spondylitis spinal score (mSASSS)]. As physical function and quality of life are considered to be hierarchically superior to spinal mobility, they were not included in the analysis. Multivariable models were built, adjusting for potential confounding. Variables with a p-value <0.10 were re-tested in the multivariable models. Six models were built, one regarding the BASMI total score and five regarding the individual components of BASMI.Results:Data from 644 patients and 5152 visits were analysed. In the multivariable analyses (table), we found an independent association between higher BASMI values and age [adjusted B (aB)=1.02, confidence interval (CI)=1.01-1.03], Ankylosing Spondylitis Disease Activity Score-C Reactive Protein (ASDAS-CRP) (aB=1.23, CI=1.15-1.32), enthesitis score (aB=1.02, CI=1.01-1.04) and MRI inflammation score (aB=1.13, CI=1.05-1.23). All individual BASMI components were independently associated with ASDAS-CRP. Apart from maximal intermalleolar distance, all other mobility measures were associated with MRI spinal inflammation. Lateral spinal flexion, cervical rotation and maximal intermalleolar distance were associated with the enthesitis score. mSASSS was associated with lateral spinal flexion and a contributory factor to tragus-to-wall distance and cervical rotation.Conclusion:In early axSpA, spinal mobility impairment is independently determined by clinical disease activity, MRI spinal inflammation and the severity of enthesitis. Maximal intermalleolar distance (which is not a true measure of spinal mobility) was the only measure not associated with MRI spinal inflammation. The influence of spinal inflammation prevails in the early phase of axSpA while spinal damage becomes more relevant in later disease stages.References:None.Disclosure of Interests:Pedro Carvalho: None declared, Ana Marreiros: None declared, Joao Eurico Fonseca: None declared, Adeline Ruyssen-Witrand Grant/research support from: Abbvie, Pfizer, Consultant of: Abbvie, BMS, Lilly, Mylan, Novartis, Pfizer, Sandoz, Sanofi-Genzyme, Pedro M Machado Consultant of: PMM: Abbvie, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, Speakers bureau: PMM: Abbvie, BMS, Lilly, MSD, Novartis, Pfizer, Roche and UCB

Intensity of spinal inflammation is associated with radiological structural damage in patients with active axial spondyloarthritis

Objective The aim was to investigate the relationship between the intensity of spinal inflammation using the apparent diffusion coefficient (ADC) and radiographic progression in axial SpA. Methods This is a cross-sectional study of participants with axial SpA and back pain. Clinical, biochemical and radiological parameters were collected. The ankylosing spondylitis disease activity score (ASDAS)-CRP was determined. Radiographic progression was represented by the modified Stoke ankylosing spondylitis spine score (mSASSS). MRI with short tau inversion recovery (STIR) and diffusion-weighted imaging sequences were performed simultaneously. Inflammatory lesions on STIR were used for the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI indexes and as references in outlining regions of interest in ADC maps to produce mean (ADCmean) and maximal (ADCmax) ADC values. Univariate and multivariate linear regression analyses were used to determine independent associations between ADC and radiographic progression. Results The 84 participants with identifiable lesions on spinal ADC maps recruited were characterized by a mean (s.d.) age of 45.01 (13.68) years, long disease duration [13.40 (11.01) years] and moderate clinical disease activity [ASDAS-CRP 2.07 (0.83)]. Multivariate regression analysis using ADCmean as the independent variable showed that age (regression coefficient [B] = 0.34; P = 0.01), male sex (B = 0.25; P = 0.04) and ADCmean (B = 0.30; P = 0.01) were positively associated with mSASSS. Multivariate regression analysis using ADCmax as the independent variable showed a tendency for ADCmax to be associated with mSASSS (B = 0.21; P = 0.07). Conclusion The intensity of spinal inflammation as determined by ADC is associated with radiographic progression in participants with active axial SpA.

Effect of tumor necrosis factor inhibition on spinal inflammation and spinal ankylosis in SKG mice

To prevent spinal progression in ankylosing spondylitis, initiating TNF-inhibitor treatment as early as possible is suggested. However, the outcomes are inconsistent in previous clinical studies. Here, we investigated the effect of TNF inhibition alone on spinal progression when used during arthritis development in a murine model. We injected 8-week-old SKG mice with curdlan (curdlan group). We injected adalimumab at 3 and 9 weeks after the first curdlan injection (ADA group). The clinical scores of peripheral arthritis decreased in the ADA group at 3 weeks after first adalimumab injection. Using positron emission tomography–magnetic resonance imaging and histologic examination, spinal inflammation was observed in the curdlan group, and was significantly deceased in the ADA group. However, spinal osteoblast activities by imaging using OsteoSense 680 EX and bone metabolism-related cytokines such as receptor activator of nuclear factor-kappa B ligand, osteoprotegerin, Dickkopf-1, and sclerostin levels except IL-17A level were not different between the two groups. We conclude that treating TNF inhibitor alone reduced peripheral arthritis score and spinal inflammation in curdlan-injected SKG mice but did not decrease the spinal osteoblast activity, suggesting little effect on spinal ankylosis.

Molecular and histologic outcomes following spinal cord injury in spiny mice, Acomys cahirinus

The spiny mouse (Acomys cahirinus) appears to be unique among mammals by showing little scarring or fibrosis after skin or muscle injury, but the Acomys response to spinal cord injury (SCI) is unknown. We tested the hypothesis that Acomys would have molecular and immunohistochemical evidence of reduced spinal inflammation and fibrosis following SCI as compared to C57BL/6 mice (Mus), which similar to all mammals studied to date exhibits spinal scarring following SCI. Initial experiments used two pathway-focused RT-PCR gene arrays (“wound healing” and “neurogenesis”) to evaluate tissue samples from the C2-C6 spinal cord 3-days after a C3/C4 hemi-crush injury (C3Hc). Based on the gene array, specific genes were selected for RT-qPCR evaluation using species-specific primers. The results supported our hypothesis by showing increased inflammation and fibrosis related gene expression (Serpine 1, Plau, Timp1) in Mus as compared to Acomys (P<0.05). RT-qPCR also showed enhanced stem cell and axonal guidance related gene expression (Bmp2, GDNF, Shh) in Acomys compared to Mus (P<0.05). Immunohistochemical evaluation of the spinal lesion at 4-wks post-injury indicated reduced collagen IV immunostaining in Acomys (P<0.05). Glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1(IBA1) immunostaining indicated morphological differences in the appearance of astrocytes and macrophages/microglia in Acomys. Collectively, the molecular and histologic results support the hypothesis that Acomys has reduced spinal inflammation and fibrosis following SCI. We suggest that Acomys may be a useful comparative model to study adaptive responses to SCI.HighlightsSpiny mice (Acomys cahirinus) and C57BL/6 (Mus) were studied after spinal injuryRT-PCR gene arrays suggested different molecular response in AcomysRTq-PCR with species-specific primers showed increased neurogenesis-related signalingHistology indicates reduced scarring and fibrosis in AcomysAcomys may be a useful comparative model to study SCI