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ID PMID Title PublicationDate abstract
28149185 Promoter polymorphism (-590, T/C) of interleukin 4 (IL4) gene is associated with rheumatoi 2017 Feb Rheumatoid arthritis (RA) is a chronic disease. It causes chronic inflammation of the joint. Recent studies suggested that interleukin 4 (IL4) contributes to susceptibility and severity of rheumatoid arthritis (RA). Especially, it was reported that promoter polymorphism (-590, T/C) of IL4 gene has been associated with susceptibility of RA. The aim of present study was to investigate whether the promoter polymorphism (-590, T/C) of IL4 gene is associated with the susceptibility of RA using meta-analysis. And in order to perform meta-analysis, comprehensive meta analysis program was used. Genetic models (co-dominant, dominant, recessive, and allele) were used to determine odds ratios (ORs), 95% confidence intervals (CIs), and P values. Nine case-control studies with case and control design were included in this meta-analysis. Overall, meta-analysis revealed a strong association with susceptibility of RA [OR = 1.303, 95% CI = 1.093-1.554, P = 0.003 in allele model (C vs. T); OR = 1.247, 95% CI = 1.054-1.474, P = 0.010 in dominant model (CC vs. CT + TT); OR = 2.148, 95% CI = 1.263-3.651, P = 0.005 in recessive model (CC + CT vs. TT)]. Our data demonstrated that promoter polymorphism (-590, T/C) of IL4 gene may be contributed to susceptibility of RA. However, more studies with a larger sample size are needed to provide more precise evidence.
26535146 Delayed-release prednisone improves fatigue and health-related quality of life: findings f 2015 OBJECTIVES: Like morning stiffness, fatigue is a common, debilitating symptom of rheumatoid arthritis (RA). Delayed-release (DR) prednisone is designed for evening administration (approximately 22:00) and releases 4 h later to coincide with the rise of nocturnal inflammatory cytokines associated with development of morning stiffness. The impact of DR prednisone on fatigue and other related patient-reported outcomes was analysed with data obtained from the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA) 2 study. METHODS: Patients with symptomatic RA (n=350) despite treatment with a disease-modifying antirheumatic drug (DMARD) were randomised 2:1 to receive additional therapy with DR prednisone 5 mg or placebo once daily for 12 weeks. Fatigue was assessed using validated instruments: the fatigue scale of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the vitality domain of the Short Form-36 (SF-36). General quality of life was assessed using the general score and individual domains of Functional Assessment of Cancer Therapy-General (FACT-G) and SF-36. RESULTS: The change from baseline to week 12 in FACIT-F score was statistically significantly different with DR prednisone/DMARD (3.8) versus placebo/DMARD (1.6; difference 2.2, p=0.0032). Improvement in FACIT-F score correlated positively with clinical response. Compared with placebo/DMARD, DR prednisone/DMARD showed a significantly greater improvement in SF-36 vitality score (5.6, p=0.001), physical component of SF-36 (2.3, p=0.0003) and general score with FACT-G (2.6, p=0.0233). CONCLUSIONS: DR prednisone in addition to a DMARD significantly improves fatigue and other aspects of health-related quality of life in patients with symptomatic RA compared with DMARD treatment alone. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00650078.
26309500 Meridian-sinew release therapy for the treatment of refractory rheumatoid arthritis. 2015 OBJECTIVE: To evaluate the efficacy and safety of Meridian-sinew Release therapy in Chinese patients with refractory active Rheumatoid Arthritis (RA). SUMMARY OF BACKGROUND DATA: Few studies focused on the effect of combination of Meridian-sinew Release therapy and Methotrexate (MTX) on refractory active RA of Chinese patients. METHODS: Eighty refractory active rheumatoid arthritis patients were randomized to receive Meridian-sinew Release+MTX 10 mg (n=40), MTX 10 mg (n=40) every week for 12 weeks. The primary end point was the proportion of patients achieving ≥20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary efficacy endpoints included 28-joint disease activity score with ESR (DAS28-ESR), simplified disease activity index (SDAI), clinical disease activity index (CDAI) and Health Assessment Questionnaire-Disability Index (HAQ-DI). RESULTS: Week 12 ACR20 response rates were significantly greater in Meridian-sinew Release+MTX group (30/38 (78.9%)) than in MTX group (19/37 (51.3%)), (P<0.001), as were ACR50 and ACR70 response rates. Patients treated with Meridian-sinew Release+MTX were significantly more likely to achieve clinical remission, using various definitions, at 12 weeks versus MTX alone. A larger percentage of Meridian-sinew+MTX patients than MTX alone patients were in states of low disease activity or remission for DAS28-ESR, SDAI and CDAI after 12 weeks of treatment. CONCLUSION: Our study suggests that Meridian-sinew Release therapy was well tolerated and efficacious in improving clinical outcomes in Chinese patients with refractory active RA.
27651921 Systematic review of patient-reported outcome measures (PROMs) for assessing disease activ 2016 Patient assessment of disease activity in rheumatoid arthritis (RA) may be useful in clinical practice, offering a patient-friendly, location independent, and a time-efficient and cost-efficient means of monitoring the disease. The objective of this study was to identify patient-reported outcome measures (PROMs) to assess disease activity in RA and to evaluate the measurement properties of these measures. Systematic literature searches were performed in the PubMed and EMBASE databases to identify articles reporting on clinimetric development or evaluation of PROM-based instruments to monitor disease activity in patients with RA. 2 reviewers independently selected articles for review and assessed their methodological quality based on the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) recommendations. A total of 424 abstracts were retrieved for review. Of these abstracts, 56 were selected for reviewing the full article and 34 articles, presenting 17 different PROMs, were finally included. Identified were: Rheumatoid Arthritis Disease Activity Index (RADAI), RADAI-5, Patient-based Disease Activity Score (PDAS) I & II, Patient-derived Disease Activity Score with 28-joint counts (Pt-DAS28), Patient-derived Simplified Disease Activity Index (Pt-SDAI), Global Arthritis Score (GAS), Patient Activity Score (PAS) I & II, Routine Assessment of Patient Index Data (RAPID) 2-5, Patient Reported Outcome-index (PRO-index) continuous (C) & majority (M), Patient Reported Outcome CLinical ARthritis Activity (PRO-CLARA). The quality of reports varied from poor to good. Typically 5 out of 10 clinimetric domains were covered in the validations of the different instruments. The quality and extent of clinimetric validation varied among PROMs of RA disease activity. The Pt-DAS28, RADAI, RADAI-5 and RAPID 3 had the strongest and most extensive validation. The measurement properties least reported and in need of more evidence were: reliability, measurement error, cross-cultural validity and interpretability of measures.
25415528 The biology of IL-23 and IL-17 and their therapeutic targeting in rheumatic diseases. 2015 Jan PURPOSE OF REVIEW: Interleukin (IL)-23 and the related cytokine IL-17 play vital roles in immune-mediated inflammatory pathology. In the years since its discovery, IL-23 has been implicated as a central pathogenic factor in multiple rheumatic conditions and has been shown to act via a wide range of immune cells including type 17 T-helper (Th17) cells and innate-like immune cells. We review here the pivotal role of these cytokines and IL-23-responsive cells in both the bona fide autoimmune rheumatic diseases rheumatoid arthritis and systemic lupus erythematosus, as well as the spondyloarthropathies which more closely resemble the auto-inflammatory conditions. RECENT FINDINGS: IL-23 and related cytokines have been found to be up-regulated in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropathy, and preclinical models suggest that they play important pathological roles in these conditions. SUMMARY: It is anticipated that agents which target the IL-23 pathway will have profound roles in modifying the natural history of these diseases and in preventing the structural damage which occurs secondary to such chronic inflammation. This is especially relevant in the case of spondyloarthropathy in which case prevention of the novel bone formation is a particular challenge. It is also potentially pertinent for patients with rheumatoid arthritis, particularly those who do not respond to other biological therapies.
27160252 APL-1, an altered peptide ligand derived from heat-shock protein, alone or combined with m 2017 May Induction of tolerance to autoantigens in vivo is a complex process that involves several mechanisms such as the induction of regulatory T cells and changes in the cytokine and chemokine profiles. This approach represents an attractive alternative for treatment of autoimmune diseases. APL-1 is an altered peptide ligand derived from a novel CD4 + T cell epitope of human heat-shock protein of 60 kDa (HSP60), an autoantigen involved in the pathogenesis of rheumatoid arthritis (RA). We have shown previously that this peptide efficiently inhibited the course of adjuvant-induced arthritis in Lewis rats and induced regulatory T cell (Treg) in ex vivo assay with PBMC isolated from RA patients. This study was undertaken to evaluate the therapeutic effect of APL-1 and its combination with methotrexate (MTX) in collagen-induced arthritis (CIA). CIA was induced in male DBA/1 mice at 8 weeks of age by immunization with chicken collagen. APL, MTX or both were administrated beginning from arthritis onset. Therapeutic effect was evaluated by arthritis and joint pathologic scores. In addition, TNFα and IL-10 in sera were measured by ELISA. Treg induction was assessed by FACS analysis. APL-1 inhibits efficiently the course of arthritis in CIA, similar to MTX. In addition, therapy with APL-1 plus MTX reduced CIA in mice, associated with an increase in Treg. These facts reinforce the therapeutic possibilities of APL-1 as a candidate drug for treatment of RA.
25868948 Radiological improvement by tocilizumab in polyarticular juvenile idiopathic arthritis. 2015 Apr Recent advances in biologic therapy have enabled reduction of the progression of destructive arthritis in rheumatoid arthritis. Once destroyed, however, the affected bones and cartilage are not fully repaired. We describe the case of an 8-year-old girl with anti-citrullinated peptide antibody (ACPA)-positive polyarticular juvenile idiopathic arthritis (p-JIA). Destructive arthritis progressed during combination therapy with infliximab, methotrexate, mizoribine and prednisolone. Clinical remission was achieved, however, after switching the biologic agent to tocilizumab, a humanized monoclonal antibody to interleukin-6 receptor. Both bone erosion and bone marrow edema on magnetic resonance imaging were repaired in association with restoration of joint spaces. Furthermore, there was no relapse of arthritis on weekly methotrexate alone for 2 years after discontinuation of the tocilizumab. Tocilizumab led to radiological repair of both bone and cartilage destruction and long-term biologics-free remission in a patient with ACPA-positive p-JIA, and should be considered for tumor necrosis factor inhibitor-resistant cases.
26184529 Lymphopenia in early arthritis: Impact on diagnosis and 3-year outcomes (ESPOIR cohort). 2015 Dec OBJECTIVES: In patients with early arthritis naive to disease-modifying antirheumatic drugs, we evaluated the prevalence of initial and persistent lymphopenia, underlying diagnoses, and risk of infection or malignancy. METHODS: Eight hundred and thirteen patients with early arthritis included in the ESPOIR cohort had a clinical examination, laboratory tests (viral serology, immunological tests, and cytokine profile), and radiographs. We determined the prevalence of lymphopenia at baseline and after 3 years, associated factors, diagnoses, and risk of infection or malignancy. RESULTS: At baseline, 50/813 (6.2%) patients had lymphopenia. Lymphopenia was associated with positive rheumatoid factor (P=0.02), cytopenia (P≤0.05), hepatitis C (P=0.05), higher C-reactive protein and DAS28 (P≤0.05 for both). Cytokine profile and radiological progression were not significantly different between patients with and without lymphopenia. Suspected diagnoses at inclusion were rheumatoid arthritis (RA, n=27), unclassified arthritis (n=15), systemic lupus erythematosus (SLE, n=3), spondyloarthritis (n=2), Sjögren's syndrome (n=1), hematologic disease (n=1), and fibromyalgia (n=1). Fifteen patients out of 42 (35.7%) with initial lymphopenia had persistent lymphopenia after 3 years, including 5 with documented causes (lupus, hepatitis C, undernutrition, azathioprine, and tamoxifen); none had PVB19, HIV, or HBV infection and none experienced infections, solid or hematologic malignancies during follow-up. Final diagnoses in these 15 patients were RA (n=6), unclassified arthritis (n=6), SLE (n=1), spondyloarthritis (n=1), and fibromyalgia (n=1). CONCLUSIONS: Lymphopenia is rare in early arthritis. The most common rheumatic cause is RA, in which marked inflammation and other cytopenias are common. Lymphopenia in early arthritis is often short-lived, even when methotrexate is prescribed.
25878651 An intractable case of suspected psoriatic arthritis combined with Dupuytren's disease. 2015 Jan Some cases of psoriatic arthritis (PsA) cannot be explicitly diagnosed, especially when the skin and nail lesions present years after the joint disease or are absent. Autoimmunity may also play a role in the development of Dupuytren's disease. However, the simultaneous presence of PsA and Dupuytren's disease is very rare. We present a patient displaying arthritis in multiple small joints, with bone erosions and bony fusions in all four extremities, combined with Dupuytren's disease. Because of the atypical clinical manifestation, the diagnosis perplexed doctors for decades. Without formal treatment, the disease followed a natural course over time. Reviewing the patient's data, a potential diagnosis of PsA, combined with Dupuytren's disease, was eventually made. After surgery, contractures of palmar and plantar fascia as well the thumb web were released, and the hallux valgus was corrected.
26606524 Rheumatoid Factor and Disease Activity Are Independent Predictors of Lymphoma in Primary S 2016 Apr OBJECTIVE: To define parameters predictive of lymphoma development in patients with primary Sjögren's syndrome (SS). METHODS: A multicenter case-control survey was performed to identify predictors of lymphoma. Cases were patients who developed lymphoma after diagnosis of primary SS and were mainly recruited through the Club Rhumatismes et Inflammation network. For each case, 2 controls (matched for disease duration and age) were randomly selected among patients with primary SS and without lymphoma. Cases and controls were compared using univariate analysis and then using multivariate analysis to identify independent predictors of lymphoma. RESULTS: One hundred one patients with primary SS and lymphoma were included. Eighty-seven patients were women (86.1%), and the mean ± SD age at lymphoma diagnosis was 57.4 ± 12.6 years. The most frequent histologic type was B cell non-Hodgkin's lymphoma (NHL) in 99 of 101 patients, with marginal-zone lymphoma in 76 of the 99 patients (76.8%) including 58 (58.6%) with lymphoma of the mucosa-associated lymphoid tissue type. Lymphomas were most frequently located in the salivary glands (43 patients). A specific treatment was initiated at diagnosis in 87 patients with B cell NHL, and 61 patients (61.6%) achieved complete sustained remission after the first line of treatment. In the multivariate analysis, salivary gland enlargement, the presence of rheumatoid factor (RF), low C4, cryoglobulinemia, lymphopenia, and disease activity according to the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (excluding the lymphoma domain) were found to be predictors of lymphoma. No previous treatment for primary SS was associated with any effect on lymphoma occurrence. CONCLUSION: In addition to previously known factors predictive of lymphoma occurrence, the independent roles of RF and disease activity were demonstrated in this case-control study of primary SS-associated lymphoma. Our findings highlight the roles of chronic antigenic stimulation and disease activity in the development of this severe complication.
27826171 Magnetic resonance imaging in inflammatory rheumatoid diseases. 2016 Magnetic resonance (MR) is used more and more frequently to diagnose changes in the musculoskeletal system in the course of rheumatic diseases, at their initial assessment, for treatment monitoring and for identification of complications. The article presents the history of magnetic resonance imaging, the basic principles underlying its operation as well as types of magnets, coils and MRI protocols used in the diagnostic process of rheumatic diseases. It enumerates advantages and disadvantages of individual MRI scanners. The principles of MRI coil operation are explained, and the sequences used for MR image analysis are described, particularly in terms of their application in rheumatology, including T1-, T2-, PD-weighted, STIR/TIRM and contrast-enhanced T1-weighted images. Furthermore, views on the need to use contrast agents to optimise diagnosis, particularly in synovitis-like changes, are presented. Finally, methods for the assessment of MR images are listed, including the semi-quantitative method by RAMRIS and quantitative dynamic examination.
26031942 Inhibition of cell adhesion and immune responses in the mouse model of collagen-induced ar 2015 Nov CD2 and CD58 are two important costimulatory molecules involved in generating the signal II required for normal immune signaling. However, this interaction can be targeted to be of benefit in cases of abnormal immune signaling seen in autoimmune diseases. Our objective in this study was to design a peptidomimetic (compound 7) based on a β-strand structure of the adhesion domain of CD2 protein to inhibit CD2-CD58 protein-protein interaction and its effect on immunomodulation in the collagen-induced arthritis (CIA) model. The ability of compound 7 to bind to CD58 protein was assessed using flow cytometry. The effect of compound 7 on modulating the immune response was evaluated in an autoimmune disease using CIA in mice. The stability of compound 7 was evaluated in mouse serum using mass spectrometry. Antibody (Ab) binding inhibition studies suggested that compound 7 binds to CD58 protein. Compound 7 was successful in modulating immune responses when administered in the CIA mouse model along with reducing anti-collagen Ab levels and decreasing the level of interferon gamma (IFN-γ) relative to control treatments. Compound 7 was found to be nonimmunogenic and stable in mouse serum up to 48 h. Results suggest that compound 7 can serve as a lead compound for immunomodulation, and could be a therapeutic agent for the autoimmune disease rheumatoid arthritis (RA).
27687484 Optimizing biological treatments for rheumatoid arthritis. 2016 Aug The area of rheumatoid arthritis (RA) treatment has been revolutionized during the last decades with the development of biological therapies and their introduction into daily clinical practice contributing greatly to this dramatic change. However, several aspects of the use of these highly effective but expensive therapies remain far from optimal. To date, there is no clear evidence for the optimal sequence of biological agents, and the choice of a second- or third-line biologic is random. The effect of drug levels and the presence of neutralizing anti-drug antibodies remain unclear. In addition, the identification of prognostic factors of response, both clinical and histopathological, is crucial for a more individualized treatment approach.
27407267 Interleukin 6 blockage-induced neutropenia in a patient with rheumatoid arthritis and reso 2015 The authors present a case report of a 59-year-old woman with rheumatoid arthritis after documented recovery from hepatitis C (HCV) infection and with resolved HBV infection who has been undergoing successful tocilizumab treatment. The patient experienced moderate to severe neutropenia after consecutive tocilizumab administrations. However, no serious infections or HBV reactivation was recorded during that period.
27081318 Reduction in Serum Uric Acid May Be Related to Methotrexate Efficacy in Early Rheumatoid A 2016 OBJECTIVES: The mechanism of action of methotrexate in rheumatoid arthritis (RA) is complex. It may increase adenosine levels by blocking its conversion to uric acid (UA). This study was done to determine if methotrexate lowers UA in early RA (ERA). METHODS: Data were obtained from Canadian Early Arthritis Cohort, an incident ERA cohort. All ERA patients with serial UA measurements were included, comparing those with methotrexate use vs. no methotrexate exposure (controls). Analyses were exploratory. Patients with concomitant gout or taking UA-lowering therapies were excluded. RESULTS: In total, 49 of the 2,524 ERA patients were identified with data available for both pre-methotrexate UA levels and post-methotrexate UA levels (300 µmol/L and 273 µmol/L, respectively; P = 0.035). The control group not taking methotrexate had a mean baseline UA level of 280 µmol/L and a follow-up level of 282 µmol/L (P = 0.448); mean change in UA with methotrexate was -26.8 µmol/L vs. 2.3 µmol/L in the no methotrexate group (P = 0.042). Methotrexate users with a decrease in UA had a disease activity score of 2.37 for 28 joints when compared with the controls (3.26) at 18 months (P = 0.042). Methotrexate users with decreased UA had a lower swollen joint count (SJC) of 0.9 at 18 months, whereas methotrexate users without lowering of UA had an SJC of 4.5 (P = 0.035). Other analyses were not significant. CONCLUSIONS: Methotrexate response is associated with lowering of serum UA in ERA compared to nonusers. This may be due to changes in adenosine levels. Methotrexate response is associated with lower UA and fewer swollen joints compared to nonresponders.
26318644 Myeloid-derived suppressor cells contribute to bone erosion in collagen-induced arthritis 2015 Dec Bone erosion is a sign of severe rheumatoid arthritis and osteoclasts play a major role in the bone resorption. Recently, myeloid-derived suppressor cells (MDSC) has been reported to be increased in collagen-induced arthritis (CIA). The number of circulating MDSCs is shown to correlate with rheumatoid arthritis. These findings suggest that MDSCs are precursor cells involved in bone erosion. In this study, MDSCs isolated from mice with CIA stimulated with M-CSF and RANKL in vitro expressed osteoclast markers and acquired osteoclast bone resorption function. MDSCs sorted from CIA mice were transferred into the tibia of normal DBA/1J mice and bones were subjected to histological and Micro CT analyses. The transferred CIA-MDSCs were shown to differentiate into TRAP(+) osteoclasts that were capable of bone resorption in vivo. MDSCs isolated from normal mice had more potent suppressor activity and much less capability to differentiate to osteoclast. Additional experiments showed that NF-κB inhibitor Bay 11-7082 or IκB inhibitor peptide blocked the differentiation of MDSCs to osteoclast and bone resorption. IL-1Ra also blocked this differentiation. In contrast, the addition of IL-1α further enhanced osteoclast differentiation and bone resorption. These results suggest that MDSCs are a source of osteoclast precursors and inflammatory cytokines such as IL-1, contributing significantly to erosive changes seen in rheumatoid arthritis and related disorders.
26333010 Prediction of Response to Therapy for Autoimmune/Inflammatory Diseases Using an Activated 2015 Oct 5 The ability to select patients who will respond to therapy is especially acute for autoimmune/inflammatory diseases, where the costs of therapies can be high and the progressive damage associated with ineffective treatments can be irreversible. In this article we describe a clinical test that will rapidly predict the response of patients with an autoimmune/inflammatory disease to many commonly employed therapies. This test involves quantitative assessment of uptake of a folate receptor-targeted radioimaging agent ((99m)Tc-EC20) by a subset of inflammatory macrophages that accumulate at sites of inflammation. Murine models of four representative inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, and atherosclerosis) show markedly decreased uptake of (99m)Tc-EC20 in inflamed lesions upon initiation of successful therapies, but no decrease in uptake upon administration of ineffective therapies, in both cases long before changes in clinical symptoms can be detected. This predictive capability should reduce costs and minimize morbidities associated with failed autoimmune/inflammatory disease therapies.
28856258 Liver involvement in children with collagen vascular diseases. 2015 Nov Liver injury such as hepatomegaly, splenomegaly and various degrees of biochemical abnormalities are quite common in children with collagen vascular diseases. They may be primary or secondary, particularly due to drug therapy (drug toxicity, fatty infiltration), superadded infections, diabetes or overlap with autoimmune hepatitis.
26893583 Rheumatoid polyarthritis suspected in an HIV patient with scleritis, peripheral ulcerative 2016 INTRODUCTION: Scleritis and peripheral ulcerative keratitis are ocular manifestations found in many inflammations and infections. Therefore, their association should prompt a search for inflammatory or infectious causes that may be life-threatening, especially in the context of AIDS due to HIV infection. FINDINGS: We report the case of a 37-year-old female, first seen in 2011 with a nodular scleritis in the right eye and a peripheral ulcerative keratitis, a necrotizing scleritis, and a granulomatous anterior uveitis in the left eye, in the context of chronic polyarthropathies that had evolved over 6 months. The patient was diagnosed with AIDS (HIV) in 2008 and was on antiretroviral therapy for the past 2 years. Ophthalmic workup was negative for opportunistic infections and potential causes of scleritis and peripheral ulcerative keratitis, and the patient was unresponsive to topical antibacterial and anti-inflammatory treatment. Ocular lesion resolution and articular swelling improvement was observed less than 6 weeks after sulfasalazine treatment. Based on American College of Rheumatology/European League Against Rheumatism classification criteria, and considering the good response to the treatment (sulfasalazine), diagnosis of rheumatoid arthritis was made in the absence of confirmatory lab tests results. CONCLUSION: In the context of ocular manifestations associated with polyarthropathies, coexisting pathologies should be considered. Diagnostic workup of chronic inflammatory rheumatism should be carried out, even in the context of HIV/AIDS.
24570026 Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythemato 2015 Jul RATIONALE: The structural and functional integrity of the endothelium is crucial in maintaining vascular homeostasis and preventing atherosclerosis. Patients with systemic lupus erythematosus (SLE) have an increased risk of developing endothelial dysfunction and premature cardiovascular disease. Neutrophil extracellular trap (NET) formation is increased in SLE and has been proposed to contribute to endothelial damage, but the mechanism remains unclear. OBJECTIVE: To determine the mechanism by which enhanced NET formation by low-density granulocytes (LDGs) in SLE contributes to endothelial damage and disrupts the endothelium. RESULTS: The putative role of NET-externalised matrix metalloproteinases (MMPs) in altering the functional integrity of the endothelium was examined. MMP-9 externalised by lupus LDGs during NET formation specifically impaired murine aortic endothelium-dependent vasorelaxation and induced endothelial cell apoptosis. Endothelial dysfunction correlated with the activation of endothelial MMP-2 by MMP-9 present in NETs, while inhibition of MMP-2 activation restored endothelium-dependent function and decreased NET-induced vascular cytotoxicity. Moreover, immunogenic complexes composed of MMP-9 and anti-MMP-9 were identified in SLE sera. These complexes, as well as anti-MMP-9 autoantibodies, induced NETosis and enhanced MMP-9 activity. CONCLUSIONS: These observations implicate activation of endothelial MMP-2 by MMP-9 contained in NETs as an important player in endothelial dysfunction, and MMP-9 as a novel self-antigen in SLE. These results further support that aberrant NET formation plays pathogenic roles in SLE.