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      Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE

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          Abstract

          Objective

          The variety of disease phenotypes among patients with SLE challenges the identification of new biomarkers reflecting disease activity and/or organ damage. Osteopontin (OPN) is an extracellular matrix protein with immunomodulating properties. Although raised levels have been reported, the pathogenic implications and clinical utility of OPN as a biomarker in SLE are far from clear. Thus, the aim of this study was to characterise OPN in SLE.

          Methods

          Sera from 240 well-characterised adult SLE cases classified according to the American College of Rheumatology (ACR) and/or the Systemic Lupus International Collaborating Clinics (SLICC) criteria, and 240 population-based controls were immunoassayed for OPN. The SLE Disease Activity Index 2000 (SLEDAI-2K) was used to evaluate disease activity and the SLICC/ACR Damage Index (SDI) to detect damage accrual.

          Results

          Serum OPN levels were in average raised fourfold in SLE cases compared with the controls (p<0.0001). OPN correlated with SLEDAI-2K, especially in patients with a disease duration of <12 months (r=0.666, p=0.028). OPN was highly associated with SDI (p<0.0001), especially in the renal (p<0.0001), cardiovascular (p<0.0001) and malignancy (p=0.012) domains. Finally, OPN associated with coherent antiphospholipid syndrome (APS; p=0.009), and both clinical and laboratory criteria of APS had significant positive impact on OPN levels.

          Conclusions

          In this cross-sectional study, circulating OPN correlates with disease activity in recent-onset SLE, reflects global organ damage and associates with APS. Longitudinal studies to dissect whether serum OPN also precedes and predicts future organ damage are most warranted.

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          Most cited references35

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          Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort

          Background and aims We studied damage accrual and factors determining development and progression of damage in an international cohort of systemic lupus erythematosus (SLE) patients. Methods The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort recruited patients within 15 months of developing four or more 1997 American College of Rheumatology (ACR) criteria for SLE; the SLICC/ACR damage index (SDI) was measured annually. We assessed relative rates of transition using maximum likelihood estimation in a multistate model. The Kaplan–Meier method estimated the probabilities for time to first increase in SDI score and Cox regression analysis was used to assess mortality. Results We recruited 1722 patients; mean (SD) age 35.0 (13.4) years at cohort entry. Patients with damage at enrolment were more likely to have further worsening of SDI (SDI 0 vs ≥1; p<0.001). Age, USA African race/ethnicity, SLEDAI-2K score, steroid use and hypertension were associated with transition from no damage to damage, and increase(s) in pre-existing damage. Male gender (relative transition rates (95% CI) 1.48 (1.06 to 2.08)) and USA Caucasian race/ethnicity (1.63 (1.08 to 2.47)) were associated with SDI 0 to ≥1 transitions; Asian race/ethnicity patients had lower rates of new damage (0.60 (0.39 to 0.93)). Antimalarial use was associated with lower rates of increases in pre-existing damage (0.63 (0.44 to 0.89)). Damage was associated with future mortality (HR (95% CI) 1.46 (1.18 to 1.81) per SDI point). Conclusions Damage in SLE predicts future damage accrual and mortality. We identified several potentially modifiable risk factors for damage accrual; an integrated strategy to address these may improve long-term outcomes.
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            Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease.

            Osteopontin (OPN) is a multifunctional molecule highly expressed in chronic inflammatory and autoimmune diseases, and it is specifically localized in and around inflammatory cells. OPN is a secreted adhesive molecule, and it is thought to aid in the recruitment of monocytes-macrophages and to regulate cytokine production in macrophages, dendritic cells, and T-cells. OPN has been classified as T-helper 1 cytokine and thus believed to exacerbate inflammation in several chronic inflammatory diseases, including atherosclerosis. Besides proinflammatory functions, physiologically OPN is a potent inhibitor of mineralization, it prevents ectopic calcium deposits and is a potent inducible inhibitor of vascular calcification. Clinically, OPN plasma levels have been found associated with various inflammatory diseases, including cardiovascular burden. It is thus imperative to dissect the OPN proinflammatory and anticalcific functions. OPN recruitment functions of inflammatory cells are thought to be mediated through its adhesive domains, especially the arginine-glycine-aspartate (RGD) sequence that interacts with several integrin heterodimers. However, the integrin receptors and intracellular pathways mediating OPN effects on immune cells are not well established. Furthermore, several studies show that OPN is cleaved by at least 2 classes of proteases: thrombin and matrix-metalloproteases (MMPs). Most importantly, at least in vitro, fragments generated by cleavage not only maintain OPN adhesive functions but also expose new active domains that may impart new activities. The role for OPN proteolytic fragments in vivo is almost completely unexplored. We believe that further knowledge of the effects of OPN fragments on cell responses might help in designing therapeutics targeting inflammatory and cardiovascular diseases.
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              The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus.

              To develop and perform an initial validation of a damage index for systemic lupus erythematosus (SLE). A list of items considered to reflect damage in SLE was generated through a nominal group process. A consensus as to which items to be included in an index was reached, together with rules for ascertainment. Each center submitted 2 assessments, 5 years apart, on 2 patients with active and 2 with inactive disease, of whom 1 had increased damage and the other had stable disease. Analysis of variance was used to test the factors physician, time, amount of damage, and activity status. Nineteen physicians completed the damage index on 42 case scenarios. The analysis revealed that the damage index could identify changes in damage seen in patients with both active and inactive disease. Patients who had active disease at both time points had a higher increase in damage. There was good agreement among the physicians on the assessment of damage in these patients. This damage index for SLE records damage occurring in patients with SLE regardless of its cause. The index was demonstrated to have content, face, criterion, and discriminant validity.
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                Author and article information

                Journal
                Lupus Sci Med
                Lupus Sci Med
                lupusscimed
                lupus
                Lupus Science & Medicine
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2053-8790
                2017
                28 July 2017
                : 4
                : 1
                : e000225
                Affiliations
                [1] departmentRheumatology/Division of Neuro and Inflammation Sciences, Department of Clinical and Experimental Medicine , Linköping University , Linköping, Sweden
                Author notes
                [Correspondence to ] Dr Lina Wirestam; lina.wirestam@ 123456liu.se
                Author information
                http://orcid.org/0000-0003-3687-8344
                http://orcid.org/0000-0002-2125-2931
                http://orcid.org/0000-0002-0153-9249
                http://orcid.org/0000-0002-6916-5490
                http://orcid.org/0000-0003-0900-2048
                Article
                lupus-2017-000225
                10.1136/lupus-2017-000225
                5704744
                29188073
                5404b555-fb82-405a-9933-7c66db65faf9
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 10 April 2017
                : 19 May 2017
                : 28 May 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003748, Svenska Sällskapet för Medicinsk Forskning;
                Funded by: Professor Nanna Svartz foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/501100007857, Stiftelsen Konung Gustaf V:s 80-Ã¥rsfond;
                Funded by: FundRef http://dx.doi.org/10.13039/501100007687, Svenska Läkaresällskapet;
                Funded by: Region Östergötland;
                Funded by: FundRef http://dx.doi.org/10.13039/501100007949, Reumatikerförbundet;
                Categories
                Biomarker Studies
                1506
                Original research article
                Custom metadata
                unlocked

                systemic lupus erythematosus,antiphospholipid syndrome,organ damage,disease activity,biomarker

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