Spondylarthropathies (including psoriatic arthritis): 244. Validity of Colour Doppler and Spectral Doppler Ultrasound of Sacroilicac Joints Againts Physical Examination as Gold Standard

Background: Sacroiliac joints (SJ) involvement is a distinctive and charasteristic feature of Spondyloarthritis (SpA) and x-ray is the test routinely used to make a diagnosis. However, x-ray reveals late structural damage but cannot detect active inflammation. The objective of this study was to assess the validity of Doppler ultrasound in SJ. Methods: Prospective blinded and controlled study of SJ, in which three populations were compared. We studied 106 consecutive cases, who were divided into three groups: a) 53 patients diagnosed with SpA who had inflammatory lumbar and gluteal pain assessed by a rheumatologist; b) 26 patients diagnosed with SpA who didn't have SJ tenderness and had normal physical examination; c) control group of 27 subjects (healthy subjetcs or with mechanical lumbar pain). All patients included that were diagnosed with SpA met almost the European Spondyloarthropathy Study Group (ESSG) classification criteria. Physical examination of the SJ included: sacral sulcus tenderness, iliac gapping, iliac compression, midline sacral thrust test, Gaenslen's test, and Patrick s test were used as gold standard. Both SJ were examined with Doppler ultrasound (General Electric Logiq 9, Wauwatosa WI, USA) fitted with a 9-14 Mhz lineal probe. The ultrasonographer was blinded to clinical data. Doppler in SJ was assessed as positive when both Doppler colour and resistance index (RI) < 0.75 within the SJ area were present. Statistical analysis was performed estimating sensitivity and specificity against gold standard. The Kappa correlation coefficient was used for reliability study. Results: 106 cases (53 female, 55 male; mean age 36 10 years) were studied. There were no statistical differences between groups related to age or sex. Physical examination of SJ was positive in 38 patients (59 sacroiliac joints). US detected Doppler signal within SJ in 37 patients (58 SJ): 33 of them were symptomatic SpA (52 SJ), one of them were asymptomatic SpA (1 SJ) and one was a healthy control (1 SJ). The accuracy of US when compared to clinical data as gold standard at subject level in the overall group was: sensitivity of 68.6% and specificity of 85.7%, positive predictive value of 70.5% and negative predictive value of 84.5%. A positive likelihood ratio of 4.8, a negative likelihood ratio of 0.36 and a kappa coefficient of 0.55 were achieved. Conclusions: Doppler US of SJ seems to be a valid method to detect active SJ inflammation. Disclosure statement: The authors have declared no conflicts of interes

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Recent advances in ankylosing spondylitis: understanding the disease and management

The term spondyloarthritis refers to a group of immune-mediated diseases characterised by inflammation of the axial skeleton, peripheral joints, and entheses. Ankylosing spondylitis (AS) is the most common and characteristic of these entities and even though it was first described over two centuries ago, the understanding of the underlying disease mechanism remains incomplete. It is known that around 40% of patients with AS have subclinical bowel inflammation, suggesting that the origin of the disease could be in the gut. Also, more genes and new molecules have demonstrated a role in the pathogenesis of AS. In this review, we analyse the latest therapies for spondyloarthritis and the most relevant discoveries over the last three years, together with their implications for different aspects of the disease

The role of B27 heavy chain dimer immune receptor interactions in spondyloarthritis.

HLA-B27 (B27) is strongly associated with spondyloarthopathy. The classical role of B27 is to present peptides from intracellular pathogens as a heterotrimeric complex with beta2 microglobulin for recognition by the T-cell receptor (TCR) of CD8 T-cells. In addition to heterotrimers, B27 can also be expressed as cell surface beta2-microglobulin (beta2m)-free homodimers (B27(2)). In addition to the TCR, MHC class I molecules bind to immunoregulatory receptors including members of the killer immunoglobulin-like receptor (KIR) and leukocyte immunoglobulin-like receptor (LILR) families. Rodents express the paired immunoglobulin receptor (PIR) family which are related to LILR. B27(2) but not beta2m-associated B27 binds to KIR3DL2 and rodent PIR. NK and T-cells expressing the immune receptor KIR3DL2, which interacts with B27(2), are expanded in B27 AS patients. Ligation of immune receptors by B27(2) promotes the survival of KIR-expressing leukocytes and modulates immune cytokine production. Upregulation ofB272 in spondyloarthritis and differential interaction of beta2m-associated HLA-B27 and B27(2) with immune receptors could be involved in the pathogenesis of B27-associated spondyloarthritis (AS)

New perspectives on the ligands and function of the killer cell immunoglobulin-like receptor KIR3DL2 in health and disease.

KIR3DL2/CD158k/p140 is a three domain killer cell immunoglobulin-like receptor incorporating cytoplasmic immunoreceptor tyrosine inhibitory motifs, expressed as a disulphide-bonded dimer. KIR3DL2 is a framework gene within the KIR locus and is highly polymorphic, with 62 allelic variants possibly coding for protein reported. KIR3DL2 binds to HLA-A3 and -A11 in a peptide-dependent fashion and to B27 free heavy chain forms. In addition, KIR3DL2 can also function as an innate immune receptor for delivery of CpG DNA to TLR9 in NK cells. The increased levels of expression of KIR3DL2 compared with other KIR expressed by T cell subsets in healthy individuals suggest it may function as a default KIR receptor. KIR3DL2-expressing natural killer (NK) cells and IL17 secreting CD4 T cells have been implicated in the pathogenesis of ankylosing spondylitis. Moreover, KIR3DL2 expression delineates circulating and cutaneous lymphoma T cells in Sézary's syndrome. Here we discuss how the unique molecular attributes of KIR3DL2 impact on its function on NK and T cells and how this may relate to its role in disease

The biochemistry and immunology of non-canonical forms of HLA-B27

HLA-B27 (B27) is strongly associated with the spondyloarthritides. B27 is expressed at the cell surface of antigen presenting cells (APC) both as canonical β2m-associated and non-canonical β2m-free heavy chain (FHC) forms which include B27 dimers (termed B272). B27 FHC forms arise in an endosomal compartment from recycling β2m-associated B27. Formation of cell surface FHC dimers is critically dependent on an unpaired reactive cysteine 67 in the α1 helix of the class I heavy chain. HLA-B27 also form redox-inducible β2m-associated dimers on exosomes and apoptosing cells. By contrast with cell surface expressed cysteine 67-dependent heavy chain dimers these dimers are dependent on a cytoplasmic cysteine 325 for their formation.HLA-B27 binds to immunoregulatory receptors including members of the Killer cell Immunoglobulin-like (KIR) and Leukocyte Immunoglobulin-like receptor family. B27 FHC bind to different but overlapping sets of these immunoreceptors compared to classical β2m-associated HLA-B27. B27 FHC bind more strongly to KIR3DL2 and LILRB2 immune receptor than other β2m-associated HLA-class I ligands. Genetic studies have implicated genes which control production of the important proinflammatory cytokine IL-17 in the pathogenesis of spondyloarthritis. Cell surface HLA-B27 FHC binding to these immune receptors or acting through other mechanisms could impact on the pathogenesis of spondyloarthritis by promoting immune cell production of IL-17. Here we review the literature on these non-canonical forms of HLA-B27 and the immune receptors they bind to and discuss the possible relevance of these interactions to the pathogenesis of spondyloarthropathy. © 2013 Elsevier Ltd