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Anti-RNP/Sm antibodies in patients with systemic lupus erythematosus and its role in thrombosis: a case-control study
Abstract
Objective
To validate the association of thrombotic events with positive lupus anticoagulant (LA) and co-presence of anti-RNP/Sm, as well as the diagnostic accuracy of this combination of antibodies for thrombosis.
Methods
Case-control study of patients with systemic lupus erythematosus (SLE) who presented thrombosis after SLE diagnosis and controls with SLE without thrombosis. Comorbidities, traditional risk factors, clinical variables, and treatment were evaluated. Antiphospholipid (aPL) and anti-RNP/Sm antibodies were determined.
Results
Sixty-three cases and 63 controls were studied, 88% women, median age of 40 years, and disease duration of 135 months at study inclusion. No differences were found between groups regarding age, comorbidities, or clinical characteristics at SLE diagnosis. Patients with thrombosis were more frequently positive for anti-RNP/Sm (p = 0.001), IgG aCL (p = 0.02), IgG anti-B2GPI (p = 0.02), IgM anti-B2GPI (p = 0.02), LA (p < 0.001), the combination of anti-RNP/Sm + LA (p < 0.001), and aPL triple marker (p = 0.002), compared to controls. The combination of anti-RNP/Sm + LA, SLEDAI-2 K, and prednisone dose was associated with thrombosis (p < 0.05). The combination of anti-RNP/Sm + LA showed 56% sensitivity, 79% specificity, 73% positive predictive value, 64% negative predictive value, positive likelihood ratio (LR) 2.69, and negative LR 0.56 for predicting thrombosis. No difference was found in the comparison of area under the curve between LA alone and the combination of anti-RNP/Sm + LA (p = 0.73).
Conclusion
Thrombosis was associated with disease activity, dose of prednisone, and the combination of anti-RNP/Sm antibodies and LA. This combination of antibodies could be useful in the identification of SLE patients at risk of thrombosis.
... A review of medical records was performed including consecutive SLE patients with and without thrombotic events from seven Rheumatologist centers that participated in the Study Group of SLE of the Sociedad Argentina de Reumatolog ıa (SAR). This study includes patients older than 16 10 aPL testing was considered to be positive only if the results were positive when examined 12 weeks apart. The medications received such as hydroxychloroquine, low doses of aspirin and oral anticoagulants were collected. ...
... [13][14][15] More studies are needed to evaluate one by one the different aPL with clinical implications. Zamora-Medina et al. 16 showed the combination of RNP/Smith antibodies plus LA was associated with thrombosis in SLE patients in multivariate analysis [OR 5.98 (95% CI 2.17-16.47); p ¼ 0.001]. ...
Introduction
Assessment of risk both for pregnancy morbidity and thrombosis in the presence of anti-phospholipid antibodies (aPL) is still a challenge in Systemic Lupus Erythematosus (SLE) patients. The Global Antiphospholipid Syndrome Score (GAPSS) takes into account the aPL profile (criteria and non-criteria aPL), the conventional cardiovascular risk factors and the autoimmune antibody profile. An adjusted model of the score (aGAPSS) excluding anti-phosphatidylserine/Prothrombin (aPS/PT), suggests that the score is able to stratify patients for their rate of events making it widely applicable in daily clinical practice.
Objective
To validate the aGAPSS in a multicentric cohort of SLE patients in Argentina.
Patients and methods
consecutive SLE patients with and with andwithout thrombotic events from seven Rheumatologist centers were included. Traditional cardiovascular risk factors, aPL antibodies and medications received (aspirin, hydroxychloroquine and anticoagulation) were collected. The score aGAPSS was calculated for each patient at the last visit by adding together the points corresponding to the risk factors: 1 for hypertension, 3 for dyslipidemia, 4 for LA and B2GPI (IgM or IgG) antibodies and 5 for aCL (IgM or IgG) antibodies. The discriminative ability of the aGAPSS was calculated by measuring the area under the receiver operating characteristic curve (AUC). Multivariate logistic regression analysis was performed to examine the impact of multiple cardiovascular risk factors and laboratory parameters on the occurrence of thrombosis.
Results
Two hundred and ninety-six SLE patients were included. One-hundred and twenty-one patients (40.9%) presented thrombotic and/or pregnancy complications. Median aGAPSS was significantly higher in patients who experienced an event (thrombosis and/or pregnancy morbidity) compared with those without [4 (IQR 1–9) versus 1 (IQR 0–5); p < 0.001]. The best cut off point for the diagnosis of thrombosis and/or pregnancy complications was aGAPSS ≥4. Multivariate logistic regression analysis showed that aCL antibodies [OR 2.1 (95% CI 1.16–3.90); p = 0.015] were an independent risk factors for thrombotic events.
Conclusions
This score is a simple tool, easy to apply to SLE patients in daily practice. The use of the aGAPSS could change the non-pharmacologic and pharmacologic treatment in higher risk patients to improve their survival.
... Interestingly, our patient also had strong positive anti-Smith muscle antibodies and antinuclear ribonucleoprotein antibody titers. In a case control study of 63 patients, anti-Smith and anti-RNP antibodies were significantly associated with thrombosis amongst patients with SLE (P=0.001) [16]. Furthermore, the patient had negative IgG anticardiolipin antibodies. ...
Background: Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is an exceptionally rare disease caused by prothrombin antibodies, resulting in reduced factor II levels. This disease can present with significant bleeding and
is usually associated with autoimmune disorders, particularly systemic lupus erythematosus (SLE). There are
currently no guidelines for the treatment of LAHPS, and corticosteroids remain the criterion standard therapy.
Pseudotumor cerebri is a disease that involves an idiopathic rise in intracranial pressure in association with
papilledema. The coexistence of pseudotumor cerebri with SLE is rare, with an overall incidence of 0.7%.
Case Report: A 16-year-old male initially presented to our hospital with nausea, headaches, and decreased visual acuity. He
was diagnosed with pseudotumor cerebri based on the findings of papilledema and a raised opening pressure
on lumbar puncture. Three months later, he presented with macroscopic hematuria and persistent epistaxis.
Further investigation revealed a prolonged activated partial thromboplastin time and prothrombin time, along
with positive LA and reduced Factor II levels, resulting in a diagnosis of LAHPS. The patient received a dose of
1 mg/kg/day of prednisolone along with hydroxychloroquine, and he had a complete recovery with cessation
of bleeding and normalization of laboratory parameters.
Conclusions: We are reporting a case of pseudotumor cerebri with a further presentation of LAHPS in a patient found to
have SLE. As both associations are rare in the presence of SLE, it is vital to recognize them early to initiate adequate management and intervention to avoid life-threatening complications.
... Positive anti-RNP antibodies have also been found to be an independent risk factor for death in patients with SLE and thrombotic microangiopathy [28]. Although the anti-RNP antibody's role in LE is unclear, it is associated with thrombosis in SLE patients, especially in the presence of lupus anticoagulant antibodies [29]. However, in this study, we did not find a link between lupus anticoagulant and LE. ...
Background
Lupus enteritis (LE), a main cause of acute abdominal pain in systemic lupus erythematosus (SLE) patients, is a serious and potentially fatal complication. This study aimed to identify clinical serological indicators to establish a nomogram to assess LE in SLE patients with gastrointestinal manifestations.
Methods
The clinical and laboratory data of SLE patients with gastrointestinal manifestations that were hospitalized in the West China Hospital from January 2010 to January 2020 were retrospectively analyzed. The least absolute shrinkage and selection operator logistic regression model was used to select potentially relevant features. Subsequently, a nomogram was developed using multivariable logistic analysis. The performance of the nomogram was evaluated using a receiver operating characteristic curve, a calibration curve, and decision curve analysis (DCA).
Findings
We included a total of 8,505 SLE patients, of which 251 had experienced gastrointestinal manifestations. The patients were randomly divided into training (n = 176) and validation (n = 75) groups. The LRA (LE Risk Assessment) model consisted of 11 significantly associated variables, which included complement 4, antineutrophil cytoplasmic antibody, albumin, anion gap, age, d-dimer, platelet, serum chlorine, anti-Sjögren's-syndrome-related antigen A, anti-ribosomal P protein, and anti-ribonucleoprotein. In the training and validation cohorts, the areas under the curve were 0.919 (95% confidence interval [CI]: 0.876–0.962) and 0.870 (95% CI: 0.775–0.964), respectively. The nomogram demonstrated excellent performance in the calibration curve and DCA.
Interpretation
The LRA model exhibits good predictive ability in assessing LE risk in SLE patients with gastrointestinal manifestations.
... [18,19] Anti-RNP antibodies are more prevalent in patients with Raynaud's phenomenon and are associated with renal involvement; [20,21] Another research reported that the combination of anti-RNP/Sm and LA was associated with thrombosis in SLE. [22] Nucleosomes and histone were considered to play a major role in the autoantibody response in LN, and circulating nucleosomes were positively correlated with an active lupus disease. [23,24] In summary, a variety of positive ANA pro le antibodies might be related to the high SDI score of LN patients, and may therefore further affect prognosis of LN. ...
Objectives: To identify and reclassify the patients in the LN cohort, and to further analyze the prominent clinical features and clinical significance of each cluster of patients.
Methods: This is a cross-sectional study of a cohort of 635 LN patients from the Rheumatology Department of Xiangya Hospital of Central South University. Demographic data, laboratory findings and clinical evaluation system include physician’s global assessment and the SLICC/ACR Damage Index were collected. Using two-step cluster analysis, patients with similar clinical property were identified and compared.
Results: Among the 635 LN patients, 599 patients (94.3%) were female. The mean age of the patients were 33.8 ± 10.4 years. Three subgroups were identified by two-step cluster analysis. Cluster 1 included 130 (20.5%) patients, Cluster 2 included 132(20.8%) patients and Cluster 3 included 373 (58.7%) patients. Cluster 3 was the largest group of mild disease activity, patients in this cluster had lower white blood cells, neutrophils, lymphocytes and mean SDI scores compared to those in the other two clusters. Cluster 1 was the smallest group of severe damage, patients in this cluster had multiple positive auto-antibodies, higher SDI scores and lower complement level. Patients of cluster 2 had the highest levels of granulocytes, but the results of other laboratory tests were roughly between the cluster 1 and cluster 3.
Conclusions: This study reclassified three groups of LN patients in a large cohort. Our research shows that the multiple positive ANA antibody may be related to the high SDI score of LN patients. Clinicians can identify patients at different stages through cluster analysis to better implement prognosis.
To analyze the clinical characteristics of cardiovascular disease in systemic lupus erythematosus (SLE) patients and identify risk factors for predicting the occurrence of cardiovascular disease in SLE patients. Clinical data of 110 SLE patients were randomly selected from the Tongde Hospital of Zhejiang Province clinical medical record database, including 50 patients with cardiovascular disease and 60 patients without. Clinical data, blood biochemistry indicators, antibody detection results, and complement levels were collected. The receiver operating characteristic (ROC) curve was used to analyze the efficacy of these differential indicators in predicting the occurrence of cardiovascular disease in SLE patients. Univariate logistic regression analysis and multivariate logistic regression analysis showed that anti-ribosomal P protein, RNP/sm, IgG, IgM, serum creatinine, uric acid, and lipoprotein a were independent risk factors for cardiovascular disease in SLE patients (P < 0.05). The area under the curve (AUC) for predicting cardiovascular disease in SLE patients using IgG was 0.67, with low sensitivity of 44% and high specificity of 88.48%. The AUC for predicting cardiovascular disease in SLE patients using IgM was 0.67, with sensitivity of 76% and specificity of 55.17%. The AUC for predicting cardiovascular disease in SLE patients using serum creatinine was 0.73, with sensitivity of 68% and specificity of 78.33%. The AUC for predicting cardiovascular disease in SLE patients using uric acid was 0.69, with sensitivity of 52% and specificity of 81.67%. The AUC for predicting cardiovascular disease in SLE patients using lipoprotein a was 0.96, with high sensitivity of 96% and specificity of 91.67%. Levels of anti-ribosomal P protein, RNP/sm, IgG, IgM, serum creatinine, uric acid, and lipoprotein A are significantly altered in SLE patients with cardiovascular disease. These indicators can be used to predict the risk of cardiovascular disease in SLE patients.
Objective:
Antiphospholipid syndrome (APS) is a leading acquired cause of thrombotic events. Although antiphospholipid antibodies have been shown to promote thrombosis in mice, the role of neutrophils has not been explicitly studied. The aim of this study was to characterize neutrophils in the context of a new model of antiphospholipid antibody-mediated venous thrombosis.
Methods:
Mice were administered fractions of IgG obtained from patients with APS. At the same time, blood flow through the inferior vena cava was reduced by induction of stenosis. Resulting thrombi were characterized for size and neutrophil content. Circulating factors and the vessel wall were also assessed.
Results:
As measured by both thrombus weight and thrombosis frequency, mice treated with IgG from patients with APS (APS IgG) demonstrated exaggerated thrombosis as compared with control IgG-treated mice. Thrombi in mice treated with APS IgG were enriched for citrullinated histone H3 (a marker of neutrophil extracellular traps [NETs]). APS IgG-treated mice also demonstrated elevated levels of circulating cell-free DNA and human IgG bound to the neutrophil surface. In contrast, circulating neutrophil numbers and markers of vessel wall activation were not appreciably different between APS IgG-treated mice and control mice. Treatment with either DNase (which dissolves NETs) or a neutrophil-depleting antibody reduced thrombosis in APS IgG-treated mice to the level in control mice.
Conclusion:
These data support a mechanism whereby circulating neutrophils are primed by antiphospholipid antibodies to accelerate thrombosis. This line of investigation suggests new, immunomodulatory approaches for the treatment of APS.
Objective
The objective of this study was to review the links between ethnicity, serology and clinical expression in systemic lupus erythematosus (SLE) in a single cohort that was followed over a 36-year period.
Patients and methods
Patients with SLE treated at the University College London Hospitals (UCLHs) between January 1978 and December 2013 formed the cohort. We assessed the demographic, clinical and serological data. Standard methods were used for laboratory testing. The Student t test and Mann–Whitney U test were used for the continuous variables; the Fisher’s exact test was used for the categorical variables.
Results
We studied 624 SLE patients: There were 571 women (91.5%), with a mean age at diagnosis of 29.0 ± 6.5 years; and 53 men (8.5%), with a mean age at diagnosis of 29.4 ± 15.3 years. Ethnically, 369 of the patients were European, 100 were Afro-Caribbean, 77 were East Asian, 56 were South Asian and 21 were of mixed ethnicity. The East Asian patients developed the disease at a younger age than the other ethnic groups (p < 0.0001). The Afro-Caribbean patients were less frequently associated with the presence of rash and photosensitivity, and the non-European patients were more likely to have alopecia and renal involvement. The South Asian patients were significantly associated with musculoskeletal and neurological involvement, serositis, Sicca syndrome and hematological features. The Afro-Caribbean patients had the highest prevalence of anti-Smith, anti-RNP, anti-Ro and anti-La antibodies. Anti-IgG anticardiolipin (aCL) antibodies were significantly associated with the non-East Asian groups; and hypocomplementemia was common in the East Asians. Rash, alopecia, mouth ulcers, serositis, neurological, joint and renal involvement were significantly associated with the presence of anti-Smith and anti-RNP antibodies in the Afro-Caribbean group. We also observed an association of joint involvement and the presence of anti-Ro and anti-La antibodies in this group.
Conclusions
The East Asian patients developed their SLE disease at a younger age than the other ethnic groups. Cutaneous involvement was more frequent in those who were not Afro-Caribbean. Serositis, joint and neurological involvement were more frequently diagnosed in the South Asian patients. Anti-ENA antibodies were frequently associated with the Afro-Caribbean patients.
Thrombotic events, both arterial and venous, are a major health concern worldwide. Further, autoimmune diseases, such as systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and antiphospholipid syndrome, predispose to thrombosis, and thereby push the risk for these morbid events even higher. In recent years, neutrophils have been identified as important players in both arterial and venous thrombosis. Specifically, chromatin-based structures called neutrophil extracellular traps (NETs) play a key role in activating the coagulation cascade, recruiting platelets, and serving as scaffolding upon which the thrombus can be assembled. At the same time, neutrophils and NETs are emerging as important mediators of pathogenic inflammation in the aforementioned autoimmune diseases. Here, we first review the general role of NETs in thrombosis. We then posit that exaggerated NET release contributes to the prothrombotic diatheses of systemic lupus erythematosus, ANCA-associated vasculitis, and antiphospholipid syndrome.
Mixed connective tissue disease (MCTD) is a rare autoimmune syndrome, signified by complex interactions between disease-related phenomena, including inflammation, proliferative vascular arteriopathy, thrombotic events and humoral autoimmune processes. It is still controversial whether MCTD is a distinct clinical entity among systemic connective tissue diseases, although several authors consider that it is distinct and underline characteristic, distinct clinical, serological and immunogenetic features. The putative target of autoimmunity in MCTD is U1-RNP, which is a complex of U1-RNA and small nuclear RNP. Both the U1-RNA component and the specific proteins, particularly U1-70K, engage immune cells and their receptors in a complex network of interactions that ultimately lead to autoimmunity, inflammation, and tissue injury. U1-RNA is capable of inducing manifestations consistent with TLR activation. Stimulation of innate immunity by native RNA molecules with a double-stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins.
Antiphospholipid antibodies (aPL), especially those targeting beta-2-glycoprotein I (β2 GPI), are well known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications. In contrast, the interaction of aPL with neutrophils has not been extensively studied. Neutrophil extracellular traps (NETs) have recently been recognized as an important activator of the coagulation cascade, as well as an integral component of arterial and venous thrombi. Here, we hypothesized that aPL might activate neutrophils to release NETs, thereby predisposing to the arterial and venous thrombosis inherent to the antiphospholipid syndrome (APS).
Neutrophils, sera, and plasma were prepared and characterized from patients with primary APS (n=52), or from healthy volunteers. No patient carried a concomitant diagnosis of systemic lupus erythematosus.
Sera and plasma from patients with primary APS have elevated levels of both cell-free DNA and NETs, as compared to healthy volunteers. Freshly-isolated APS neutrophils are predisposed to high levels of spontaneous NET release. Further, APS-patient sera, as well as IgG purified from APS patients, stimulate NET release from control neutrophils. Human aPL monoclonals, especially those targeting β2 GPI, also enhance NET release. The induction of APS NETs can be abrogated with inhibitors of reactive oxygen species formation and toll-like receptor 4 signaling. Highlighting the potential clinical relevance of these findings, APS NETs promote thrombin generation.
Neutrophil NET release warrants further investigation as a novel therapeutic target in APS. This article is protected by copyright. All rights reserved.
© 2015, American College of Rheumatology.
Introduction
Anti-RNP autoantibodies occur either in mixed connective tissue disease (MCTD) (with a frequently favorable prognosis), or in systemic lupus erythematosus (SLE) cases with aggressive major organ disease. It is uncertain how to assess for the risk of severe disease in anti-RNP + patients.
Methods
Following institutional review board-approved protocols, clinical data and blood were collected from patients with known or suspected anti-RNP autoimmunity and normal controls in a cohort study. Samples were screened for parameters of immune activation. Groups were compared based on clinical diagnoses, disease classification criteria, disease activity and specific end-organ clinical manifestations.
Results
Ninety-seven per cent of patients satisfying Alarcon-Segovia MCTD criteria also met Systemic Lupus International Collaborating Clinic (SLICC) SLE criteria, while 47% of the anti-RNP + SLE patients also met MCTD criteria. Among SLICC SLE patients, MCTD criteria were associated with reduced rates of renal disease (odds ratio (OR) 4.3, 95% confidence interval (CI) 1.3–14.0), increased rates of Raynaud's phenomenon (OR 3.5, 95% CI 1.3–9.5) and increased serum B-cell maturation antigen, transmembrane activator and CAML interactor and TNFα levels. Circulating immune markers and markers of type I interferon activation were not effective at distinguishing clinical subgroups.
Conclusions
Among anti-RNP patients, the question of MCTD versus SLE is not either/or: most MCTD patients also have lupus. MCTD classification criteria (but not a broad set of immune markers) distinguish a subset of SLE patients at reduced risk for renal disease.
Antibodies to prothrombin can be detected by ELISA using prothrombin coated onto irradiated plates (aPT) or the phosphatidylserine/prothrombin complex as antigen (aPS/PT) and they have been both related with the clinical manifestation of APS. Current evidence supports the concept that they belong to distinct populations of autoantibodies. Nevertheless, they can both be detected simultaneously in one patient.
This mini-review will focus on data available on aPS/PT antibodies and their clinical utility in the diagnosis of APS.
Objectives
The long-term prognosis of individuals fulfilling the laboratory criteria, but not clinical criteria, of antiphospholipid syndrome (APS) has not been widely investigated. The primary aim of this study was to evaluate the incidence of first thrombotic event (deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), stroke or transient ischaemic attack (TIA) in a nationwide antiphospholipid antibody (aPL) carrier cohort.
Design
We conducted a prospective nationwide cohort study.
Setting
The aPL profile of participants was recorded from the laboratory database. Information was collected about thrombotic and pregnancy complications, subsequent medical history, other risk factors for thrombosis, use of prophylactic antithrombotic medication and general health.
Participants
Participants included adult asymptomatic aPL carriers recognized in Finland during 1971–2009.
Main outcome measure
The main outcome measure was incidence of first thrombotic event.
Results
A total of 119 (89% female) aPL carriers were followed for mean (SD) of 9.1 (7.5) years (range 3–41 years). Sixty-one per cent of the study participants had autoimmune disease, most often systemic lupus erythematosus (SLE). Thirty-six of 119 (30%) were either double or triple positive, 56% single lupus anticoagulant (LA) positive, and 8% and 5% single anticardiolipin antibodies (aCL) and anti-β2glycoprotein I antibodies (aβ2GPI) positive, respectively. Nine (7.6%) study patients experienced a first thrombotic event (five DVT, one PE, two MI, one TIA) mean (SD) 7.2 (8.3) years (range 1–26 years) after aPL detection (annual incidence rate 0.8%). All individuals who developed thrombotic complications had autoimmune disease. Annual rate of first thrombotic event in carriers of single positivity (0.65%) was equal to the known risk of thrombosis in the healthy Caucasian population, whereas the rate was two times higher in carriers of double or triple positivity (1.27%). Sixteen of 79 (20%) women experienced pregnancy complications.
Conclusions
Double or triple positivity for aPL is a risk factor for future thrombotic events, especially in individuals with an underlying autoimmune disease, whereas single positivity does not seem to carry an elevated risk of thrombosis.
For almost 20 years, apoptosis and secondary necrosis have been considered the major source of autoantigens and endogenous adjuvants in the pathogenic model of systemic autoimmune diseases. This focus is justified in part because initial evidence in systemic lupus erythematosus (SLE) guided investigators toward the study of apoptosis, but also because other forms of cell death were unknown. To date, it is known that many other forms of cell death occur, and that they vary in their capacity to stimulate as well as inhibit the immune system. Among these, NETosis (an antimicrobial form of death in neutrophils in which nuclear material is extruded from the cell forming extracellular traps), is gaining major interest as a process that may trigger some of the immune features found in SLE, granulomatosis with polyangiitis (formerly Wegener’s granulomatosis) and Felty’s syndrome. Although there have been volumes of very compelling studies published on the role of cell death in autoimmunity, no unifying theory has been adopted nor have any successful therapeutics been developed based on this important pathway. The recent inclusion of NETosis into the pathogenic model of autoimmune diseases certainly adds novel insights into this paradigm, but also reveals a previously unappreciated level of complexity and raises many new questions. This review discusses the role of cell death in systemic autoimmune diseases with a focus on apoptosis and NETosis, highlights the current short comings in our understanding of the vast complexity of cell death, and considers the potential shift in the cell death paradigm in autoimmunity. Understanding this complexity is critical in order to develop tools to clearly define the death pathways that are active in systemic autoimmune diseases, identify drivers of disease propagation, and develop novel therapeutics.
Persistent antiphospholipid (aPL) antibodies are occasionally found in subjects without prior history of thromboembolic events (TEs), raising the dilemma of whether to initiate or not a primary thromboprophylaxis. A first TE is considered rare in aPL carriers, but previous studies did not consider the aPL profile nor was the test positivity confirmed in a reference laboratory. In this study, 104 subjects with high-risk aPL profile (positive lupus anticoagulant, anticardiolipin, and anti-β(2)-glycoprotein I antibodies, triple positivity) confirmed in a reference laboratory, were followed up for a mean of 4.5 years. There were 25 first TEs (5.3% per year): the cumulative incidence after 10 years was 37.1% (95% confidence interval [CI], 19.9%-54.3%). On multivariate analysis, male sex (hazard ratio = 4.4; 95% CI, 1.5-13.1, P = .007) and risk factors for venous thromboembolism (hazard ratio = 3.3; 95% CI, 1.3-8.5, P = .01) were independent predictors for TEs. Aspirin did not significantly affect the incidence of TE. In conclusion, the occurrence of a first TE in carriers of high-risk aPL profile is considerable; it is more frequent among male subjects and in the presence of additional risk factors for venous TE. These data can help in the decision to initiate primary thromboprophylaxis in these subjects.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)-induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)-dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid-recognizing antibodies and type I IFN production in this disease.
We studied antiphospholipid antibodies (aPL) in blood samples from a cohort of individuals followed for thrombosis to determine whether the persistent presence of anticardiolipin antibodies (aCL) is associated with a greater likelihood of having lupus anticoagulant and/or anti-beta2-glycoprotein I antibodies (LA/abeta2GPI).
Blood samples from 353 individuals who had been tested for aCL on at least two occasions were tested for abeta2GPI and LA. Two groups were defined: aCL-persistent, who tested aCL-positive on at least two occasions, and aCL non-persistent, who tested aCL-positive on fewer than two occasions. Multivariate logistic regressions were performed using LA/abeta2GPI, LA and abeta2GPI as outcome variables and the percentage of aCL-positive tests as the predictor variable, adjusted for age, gender, family history of cardiovascular disease (CVD), systemic lupus erythematosus (SLE), smoking and number of venous (VT) and arterial thromboses (AT).
Sixty-eight (19%) individuals were aCL persistent and 285 (81%) were aCL non-persistent. LA/abeta2GPI was found in 36 (53%) of the aCL persistent group and 38 (13%) of the aCL non-persistent group. The two groups were similar for age, gender and smoking. Family history of CVD, SLE, VT and AT were more frequent in the aCL persistent group. Multivariate analyses revealed that odds ratios for LA/abeta2GPI, LA and abeta2GPI were 1.34 [95% confidence interval (CI) = 1.22-1.47], 1.36 (95% CI = 1.24-1.50) and 1.47 (95% CI = 1.31-1.65) respectively for each 10% increase in aCL-positive tests vs 0% positive tests.
Persistence of aCL positivity is associated with an increased risk of LA/abeta2GPI.
Antiendothelial cell antibodies (AECA) are a heterogeneous family of antibodies reacting with endothelial cell antigens. These antibodies are found in various diseases and recognise several antigen determinants. Different pathophysiological effects have been observed in in vitro experiments, which include direct or indirect cytotoxicity and endothelial cell apoptosis. Furthermore, some AECA activate endothelial cells, resulting in increased leucocyte adhesiveness, activation of coagulation and vascular thrombosis. In animal models, it has been shown that AECA could promote vascular damage. Neither the endothelial cell antigens nor their precise role in the pathogenecity of different diseases in which AECA are found is well characterised. Nowadays, it is not known whether AECA are an epiphenomenon accompanying vascular injury or whether they are pathogenic. It is controversial whether fluctuations in AECA titres are associated with disease activity during follow-up studies. This review summarises the present knowledge about AECA, AECA antigens and their potential role in the pathogenecity of vasculitis and connective tissue diseases.
The objective of this study was to characterize risk factors for thrombotic events in lupus patients. A total of 272 lupus patients were followed up for five years during which the presence of aPL antibodies [anticardiolipin (aCL), anti-beta2-glycoprotein I (aβ2GPI) and lupus anticoagulant (LAC)] were determined, and all thrombotic incidents and antithrombotic therapy-related data were collected. At baseline, three groups were constituted, an aPL–group with 107 aPL negative patients, an aPL+ group with 81 aPL positive patients without clinical thrombosis and a secondary antiphospholipid syndrome (APS) group with 84 aPL+ patients who met the Sapporo criteria. LAC was more common in the APS than the aPL+ group (32.1% versus 9.9%, P < 0.001). The prevalence of clinical thrombotic events was significantly higher when all three types of aPL were present compared to only aCL positive cases. During follow up, aPL appeared in 7.5% of the aPL - group, and 2.8% of this group had thrombotic complications. In the aPL + group, thrombotic events reoccurred in 1.9% of those receiving antithrombotic prophylaxis and 6.9% of those without primary prophylaxis. Despite anticoagulant therapy, thrombotic events reoccurred in 8.3% of the APS group. These findings indicate that LAC, constant and cumulative presence of aPL and previous thrombosis are positive predictors for the development of thrombotic complication in lupus patients.
The antiphospholipid syndrome is a systemic autoimmune disease defined by thrombotic or obstetrical events that occur in patients with persistent antiphospholipid antibodies.1 Thrombotic antiphospholipid syndrome is characterized by venous, arterial, or microvascular thrombosis. Patients with catastrophic antiphospholipid syndrome present with thrombosis involving multiple organs.2 Obstetrical antiphospholipid syndrome is characterized by fetal loss after the 10th week of gestation, recurrent early miscarriages, intrauterine growth restriction, or severe preeclampsia.1 The major nonthrombotic manifestations of antiphospholipid- antibody positivity include valvular heart disease, livedo, antiphospholipidantibody- related nephropathy, thrombocytopenia, hemolytic anemia, and cognitive dysfunction. The antiphospholipid syndrome is often associated with other systemic autoimmune diseases such as systemic lupus erythematosus (SLE); however, it commonly occurs without other autoimmune manifestations (primary antiphospholipid syndrome). Although criteria for classification of the antiphospholipid syndrome have been proposed, 1 the definition of clinically significant antiphospholipid-antibody positivity is not well established, and thrombosis is generally multifactorial. Our objectives are to help both general practitioners and specialty-based physicians recognize and accurately diagnose the antiphospholipid syndrome, as well as to provide basic recommendations for the treatment of patients who are persistently positive for antiphospholipid antibodies. Given the limited number of well-designed, randomized, controlled trials, our recommendations are evidence-based whenever possible but often reflect expert opinion.
Objective:
Recently, our group conceived a risk score for clinical manifestations of APS (the global APS score, or GAPSS) that takes into account the combination of independent cardiovascular risk factors and the aPL positivity profile. These include hyperlipidaemia, arterial hypertension, aCL, anti-β2 glycoprotein-I, aPS-PT and the LA. A complementary version, the adjusted GAPSS (aGAPSS), which excludes aPS-PT, was also designed. The aim of our study was to systematically review the literature to assess the clinical utility of the GAPSS and aGAPSS for risk stratification of any APS clinical manifestation.
Methods:
We pooled data from available cohort studies, including a total of 10 studies, comprising 2273 patients, in which the GAPSS has been applied. A search strategy was developed a priori to identify an available cohort that reported findings which investigated the clinical utility of GAPSS or aGAPSS.
Results:
Seven studies used the GAPSS in their cohort, whereas three studies used the aGAPSS. In brief, we found a statistically significant difference in the cumulative GAPSS and aGAPSS between patients that experienced an arterial and/or venous thrombotic event [cumulative mean GAPSS ( s . d .) 10.6 (4.74) and aGAPSS 7.6 (3.95)], patients without any thrombotic manifestation [cumulative GAPSS 7.01 (5.46) and aGAPSS 4.9 (4.33)] and patients with pregnancy morbidity [cumulative GAPSS 8.79 (2.59) and aGAPSS 6.7 (2.8)]. The highest levels of GAPSS were found in patients that experienced arterial thrombosis [mean GAPSS 12.2 (5.2)] and patients that experienced any recurrences of clinical manifestations of APS [mean GAPSS 13.7 (3.1)].
Conclusion:
GAPSS may represent a useful tool to assess the thrombosis or pregnancy loss risk in aPL-positive patients, switching from the concept of aPL as a sole diagnostic antibody to aPL as risk factors for clinical events.
Objective:
The incidence of thrombosis in patients with systemic lupus erythematosus (SLE) is 25 to 50-fold higher than in the general population; we aimed to define the characteristics of venous thrombotic events (VTE) and arterial thrombotic events (ATE) to identify the patients at highest risk.
Methods:
The study included 219 patients with recent-onset SLE. At baseline, standardized medical history and laboratory tests were done. Followup visits occurred quarterly, and information about damage accrual, comorbidities, and cardiovascular risk factors was updated annually. Main outcome was development of TE after SLE diagnosis.
Results:
Thirty-five patients (16%) developed TE (27 VTE, 8 ATE) during 5.21 years of followup; incidence rate 31/1000 patient-years. Most events (57%) developed within the first year of diagnosis, and 69% were not associated with lupus anticoagulant (LAC), determined with 1 method. VTE developed earlier than ATE (2.0 vs 57.5 mos, p = 0.02). In the multivariate analysis, variables preceding VTE included cutaneous vasculitis, nephrotic syndrome, dose of prednisone, and LAC in combination with anti-RNP/Sm antibodies (p < 0.03). Patients with ATE were older (median age 44 vs 29 yrs, p = 0.04), smokers, and had hypertension, diabetes mellitus, dyslipidemia, at least 2 traditional risk factors, nephrotic syndrome, chronic damage, and a higher cumulative dose of prednisone (p < 0.05). LAC in combination with anti-RNP/Sm antibodies was associated with VTE and improved the accuracy for predicting it.
Conclusion:
Our study suggests that in SLE, VTE and ATE have different risk factors. Understanding these differences is helpful for identifying patients at highest risk. The use of LAC plus anti-RNP/Sm for predicting VTE deserves further study.
In this review, we examine the evidence that neutrophil extracellular traps (NETs) play a critical role in innate immunity. We summarize how NETs are formed in response to various stimuli and provide evidence that NETosis is not universally a cell-death pathway. Here we describe at least two different mechanisms by which NETs are formed, including a suicide lytic NETosis and a live cell or vital NETosis. We also evaluate the evidence for NETs in catching and killing pathogens. Finally, we examine how infections are related to the development of autoimmune and vasculitis diseases through unintended but detrimental bystander damage resulting from NET release.
Objective. To test the reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in the assessment of patients with SLE.
Methods. Ten patients with SLE, representing a spectrum of damage and activity, were included. Each patient was examined by 6 of 10 physicians from 5 countries, representing 10 lupus clinics. The SLICC/ACR Damage Index was used to assess accumulated damage, and the SLEDAI was used to assess disease activity. The order of the patients and physicians was randomized according to a Youden square design.
Results. The SLICC/ACR Damage Index detected differences among patients ( P < 0.001). There was no detectable observer difference ( P = 0.933), and there was no order effect ( P = 0.261). Similar results were obtained with the SLEDAI. There was concordance in the SLICC/ACR Damage Index among observers, despite a wide spectrum of disease activity detected by the SLEDAI.
Conclusion. Physicians from different centers are able to assess patients with SLE in a reproducible way, using the SLEDAI to assess disease activity and the SLICC/ACR Damage Index to assess accumulated damage.
The main laboratory characteristic of lupus anticoagulants (LA) is their ability to prolong phospholipid-dependent clotting time in vitro. The laboratory demonstration of LA requires a systematic approach combined with an awareness of the many variables that can affect test results. The ideal testing procedures are those sensitive enough to detect weak LA and specific enough so as not to produce incorrect conclusions. International guidelines have been published to assist laboratories in applying correct testing processes. The most recently published guidelines from the International Society on Thrombosis and Haemostasis update the criteria for detecting the presence of LA that were presented in the 1995 guidelines. Some of the specific recommendations relate to the key areas of setting cut-off levels for screening, mixing, and confirmatory procedures. The more challenging aspects of testing for LA include maintaining sensitivity and specificity of the assays, especially in the presence of anticoagulant therapy.
Antiphospholipid antibody syndrome (APS) is an autoimmune thrombophilia mediated by autoantibodies directed against phospholipid-binding plasma proteins, mainly β2 Glycoprotein I (β2GPI)-a plasma apolipoprotein and prothrombin (PT). A subgroup of these antibodies termed "Lupus Anticoagulant" (LA) elongate in vitro the clotting times, this elongation not corrected by adding normal plasma in the detection system. The exact mechanism by which these autoantibodies induce thrombosis is not well understood. Resistance to natural anticoagulants such as protein C, impaired fibrinolysis, activation of endothelial cells to a pro-coagulant phenotype and activation of platelets, are among the mechanisms partially supported by experimental evidence. Artificially dimerized β2GPI binds tightly to platelet membrane activating them. We search for mechanisms of natural dimerization of β2GPI by proteins of the platelet membranes and found that platelet factor 4 (PF4) assembled in homotetramers binds two molecules of β2GPI and this complex is recognized by anti-β2GPI antibodies, the whole complexes being thrombogenic in terms of activating platelets as confirmed by p38MAP kinase phosphorylation and thromboxane B2 production. Of note PF4/heparin complexes are also immunogenic triggering the production of anti-PF4/heparin antibodies which activate also platelets (the so-called "heparin-induced thrombocytopenia and thrombosis syndrome", HITT). The anti-β2GPI antibodies activate platelets by their F(ab)2, while the anti-PF4/heparin by their Fc fragments. Thus PF4 is a common denominator in the pathogenesis of APS and HITT which share also clinical characteristics such as thrombocytopenia and thrombosis.
The objective is to study the annual incidence and standardized incidence ratio (SIR) of venous thromboembolism (VTE) in a cohort of Chinese patients with systemic lupus erythematosus (SLE). VTE events of SLE patients occurring between 1999 and 2008 were identified from our database, and the annual incidence of VTE was calculated according to the cohort size. SIRs were estimated by the ratios of the incidence of VTE in SLE to the general population. In 2008, 516 SLE patients were in our cohort. The mean age of SLE onset was 32.2 +/- 14 years and the duration of SLE was 9.3 +/- 8.8 years. Fifty-seven percent of the patients had disease duration of > or =5 years. Between 1999 and 2008, 18 episodes of VTE occurred in 14 patients. The incidence of VTE did not show significant fluctuation and the mean annual incidence was 4.2/1,000 patient-year. The reported VTE events were: popliteal vein thrombosis (56%), pulmonary embolism (22%), renal vein, retinal vein, subclavian vein and dural sinus thrombosis (5.6% each). The cumulative risks of VTE since SLE diagnosis were 2.8% and 3.7% at 5 and 10 years, respectively. Compared to the general population, the mean SIR of VTE in SLE patients within this period was 11.9 (7.31-19.6; p < 0.001). The SIR of VTE was highest in patients under the age of 30 years. The presence of the antiphospholipid antibody was independently associated with VTE (HR 4.36 [1.67-11.4]; p = 0.003). Although venous thrombosis is uncommon in Chinese, Chinese patients with SLE are 12 times more prone to VTE than the general population.
The characteristics and the clinical course of antiphospholipid syndrome (APS) in high-risk patients that are positive for all three recommended tests that detect the presence of antiphospholipid (aPL) antibodies have not been described.
This retrospective analysis of prospectively collected data examined patients referred to Italian Thrombosis Centers that were diagnosed with definite APS and tested positive for aPL [lupus anticoagulant (LA), anti-cardiolipin (aCL), and anti-beta2-glycoprotein I (beta2GPI) antibodies]. Laboratory data were confirmed in a central reference laboratory.
One hundred and sixty patients were enrolled in this cohort study. The qualifying events at diagnosis were venous thromboembolism (76 cases; 47.5%), arterial thromboembolism (69 cases; 43.1%) and pregnancy morbidity (11 cases; 9.7%). The remaining four patients (2.5%) suffered from catastrophic APS. The cumulative incidence of thromboembolic events in the follow-up period was 12.2% (95% CI, 9.6-14.8) after 1 year, 26.1% (95% CI, 22.3-29.9) after 5 years and 44.2% (95% CI, 38.6-49.8) after 10 years. This was significantly higher in those patients not taking oral anticoagulants as compared with those on treatment (HR=2.4 95% CI 1.3-4.1; P<0.003). Major bleeding associated with oral anticoagulant therapy was low (0.8% patient/years). Ten patients died (seven were cardiovascular deaths).
Patients with APS and triple positivity for aPL are at high risk of developing future thromboembolic events. Recurrence remains frequent despite the use of oral anticoagulants, which significantly reduces the risk of thromboembolism.
One of the conclusions of the subcommittee meeting on Lupus Anticoagulant/Phospholipid dependent antibodies, held in Geneva on 2007, was the need to update the guidelines on Lupus Anticoagulant (LA) detection. Particular emphasis was given to several aspects discussed in this official communication. A new paragraph is dedicated to the patient selection, and aims to minimize inappropriate requests for LA testing. Modalities for blood collection and processing are fully delineated and the choice of tests is limited to dRVVT and a sensitive aPTT. Calculation of cut-off values for each diagnostic step are clearly stated. A final paragraph reports the interpretation of the results in general and in particular situations.
Antiphospholipid antibodies (aPL), namely anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC), have been associated with an increased risk of thrombosis in systemic lupus erythematosus (SLE). We examined additional thrombosis risk factors (aPL profile, SLE-related, and traditional risk factors) and the primary thrombosis prevention in SLE patients with and without aPL.
All SLE patients with positive aPL but without previous thrombotic manifestations who were regularly followed up at our department (n = 144) and 144 age- and sex-matched SLE patients with negative aPL were included in this study. The median followup times were 104 and 112 months, respectively. The demographic, clinical, laboratory, and treatment characteristics and the traditional thrombosis risk factors were recorded.
The thrombosis rate was 29 per 144 aPL-positive patients (20.1%) and 11 per 144 aPL-negative patients (7.6%; P = 0.003). In multiadjusted analysis, significant predictors of thrombosis were male sex (hazard ratio [HR] 6.25, P < 0.01), LAC (HR 3.48, P = 0.04), and constantly positive aCL (HR 5.87, P = 0.01) for aPL-positive patients, while male sex (HR 7.14, P = 0.03) and hypertension were predictors for aPL-negative patients (HR 6.49, P = 0.03). Additionally, the duration of low-dose aspirin treatment played a protective role against thrombosis in aPL-positive patients (HR per month 0.98, P = 0.05), as did the duration of hydroxychloroquine in both aPL-positive (HR per month 0.99, P = 0.05) and aPL-negative patients (HR per month 0.98, P = 0.04).
Independent predictors of thrombosis for aPL-positive patients were male sex, LAC, and constantly positive aCL, and for aPL-negative patients were male sex and hypertension. The duration of low-dose aspirin use played a protective role against thrombosis in aPL-positive patients as did the duration of hydroxychloroquine in both groups.
To determine the risk of thrombosis in patients with systemic lupus erythematosus (SLE) and other autoimmune diseases of recent onset.
A retrospective cohort of 482 patients, mean age 28.3 years, with SLE or other autoimmune diseases was analyzed. Followup started at diagnosis or first appointment within 12 months since diagnosis until the development of thrombosis, end of study, loss to followup, or death. Thromboses were diagnosed upon clinical manifestations and confirmed by appropriate studies. Clinical variables were retrieved from the medical records, and SLE activity was assessed from the medical notes at onset of thrombosis, or at a dummy date for thrombosis, using the SLE Disease Activity Index-2K.
During 2936 patient-years of followup, thromboses occurred in 49 patients (20.3%) with SLE and 6 patients (2.5%) with other autoimmune diseases. The incidence rate of thrombosis was 36.3 and 3.8 per 1000 patient-years in SLE and in other autoimmune diseases, respectively; relative risk 9.6 (95% CI 4.1-27.4, p<0.0001). Throughout the disease course, the risk of thrombosis remained high in the SLE group, while in patients with other autoimmune diseases this risk was lower. The incidence of venous and arterial thrombosis was similar among SLE patients and patients with other autoimmune diseases. SLE and venous insufficiency were associated with thromboses in the total study population, and with venous insufficiency, vasculitis, and disease activity in the SLE group.
Patients with autoimmune diseases, particularly SLE, are at an increased risk of thrombosis. In patients with SLE, the risk remains elevated throughout the course of the disease.
Few studies have examined thrombosis in systemic lupus erythematosus (SLE), none have included Asian-Americans, and most have had small sample sizes. We analysed risk factors for thrombosis in a large, multi-ethnic SLE cohort.
We studied 1930 SLE subjects, including Caucasians, African-Americans, Asian-Americans and Hispanics. Data were derived from questionnaires and medical records. Documented history of thrombosis was the primary outcome. Explanatory variables included age at SLE diagnosis, gender, ethnicity, disease duration, smoking, antiphospholipid antibody (aPL) status, nephritis and specific medications.
Smoking (OR 1.26, p = 0.011), longer disease duration (OR 1.26 per 5 years p = 0.027 x 10(-7)), nephritis (OR 1.35, p = 0.036), aPL positivity (OR 3.22, p<10(-9)) and immunomodulating medication use (OR 1.40, p = 0.011) were statistically significant risk factors for thrombosis. Younger age at SLE onset was protective (OR 0.52 for age </=20, p = 0.001). After adjusting for disease severity and incorporating propensity scores, hydroxychloroquine use remained significantly protective for thrombosis (OR 0.62, p = 4.91 x 10(-4)).
This study confirms that older age at onset, longer disease duration, smoking, aPL positivity, history of nephritis and immunomodulating medication use are risk factors for thrombosis in SLE. These data are the first to confirm in a large and ethnically diverse SLE cohort that hydroxychloroquine use is protective for thrombosis.
The 1971 preliminary criteria for the classification of systemic lupus erythematosus (SLE) were revised and updated to incorporate new immunologic knowledge and improve disease classification. The 1982 revised criteria include fluorescence antinuclear antibody and antibody to native DNA and Sm antigen. Some criteria involving the same organ systems were aggregated into single criteria. Raynaud's phenomenon and alopecia were not included in the 1982 revised criteria because of low sensitivity and specificity. The new criteria were 96% sensitive and 96% specific when tested with SLE and control patient data gathered from 18 participating clinics. When compared with the 1971 criteria, the 1982 revised criteria showed gains in sensitivity and specificity.
Vascular damage in systemic lupus erythematosus (SLE) occurs through vasculitis, premature atherosclerosis, and hypercoagulability (predominantly due to the antiphospholipid antibody syndrome). In the Hopkins Lupus Cohort, a prospective cohort study, the incidence of thrombosis is 2 per 100 person-years of follow-up. Markers of immune-complex mediated injury (high anti-dsDNA and low C3), atherosclerosis (hypertension, hyperlipidemia, homocysteine) and antiphospholipid antibodies (lupus anticoagulant or anticardiolipin) are independent predictors of thrombosis. Hydroxychloroquine use is protective against future thrombosis.
To test the reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in the assessment of patients with SLE.
Ten patients with SLE, representing a spectrum of damage and activity, were included. Each patient was examined by 6 of 10 physicians from 5 countries, representing 10 lupus clinics. The SLICC/ACR Damage Index was used to assess accumulated damage, and the SLEDAI was used to assess disease activity. The order of the patients and physicians was randomized according to a Youden square design.
The SLICC/ACR Damage Index detected differences among patients (P < 0.001). There was no detectable observer difference (P = 0.933), and there was no order effect (P = 0.261). Similar results were obtained with the SLEDAI. There was concordance in the SLICC/ACR Damage Index among observers, despite a wide spectrum of disease activity detected by the SLEDAI.
Physicians from different centers are able to assess patients with SLE in a reproducible way, using the SLEDAI to assess disease activity and the SLICC/ACR Damage Index to assess accumulated damage.
In order to elucidate the pathogenic role(s) of autoantibodies in connective tissue disease (CTD), we examined whether autoantibodies against U1-ribonucleoprotein (RNP) and double-stranded (ds) DNA can up-regulate ICAM-1, ELAM-1 and class I and II MHC molecule expression on pulmonary artery endothelial cells (HPAEC). ICAM-1, ELAM-1 and class II MHC molecule expression on HPAEC cultured in the presence of anti-U1-RNP-containing and anti-dsDNA-containing IgG from CTD patients was up-regulated significantly in comparison with that on HPAEC cultured with IgG from normal healthy volunteers. Affinity chromatographic enrichment and depletion of the anti-U1-RNP antibody content of anti-U1-RNP-containing IgG confirmed that the anti-U1-RNP antibody did up-regulate ICAM-1, ELAM-1 and class II MHC molecule expression. The finding that an IgG F(ab')2-purified anti-U1-RNP antibody also up-regulated expression of these molecules may indicate that mechanisms other than Fc receptor-mediated stimulation are involved. These in vitro findings suggest that autoantibodies against U1-RNP and dsDNA play important roles in the immunopathological processes leading to the proliferative pulmonary arterial vasculopathy observed in CTD patients with pulmonary hypertension by up-regulating adhesion and class II MHC molecule expression on endothelial cells.
In order to elucidate the immunological properties of anti-U1-ribonucleoprotein (RNP) antibody, one of the autoantibodies detected in patients with connective tissue diseases (CTDs), we tested the endothelial cell-binding by anti-U1-RNP antibodies and epitopes on human pulmonary artery endothelial cells (HPAECs) to which the autoantibody bound. IgG fractions positive for anti-U1-RNP from patients with CTDs bound to the HPAECs. Furthermore, intact and F(ab')2 IgG anti-U1-RNP purified by affinity chromatography also bound to endothelial cells. The binding activity of IgG fractions positive for anti-U1-RNP to the endothelial cells could be effectively absorbed by U1-RNP-Sepharose. An immunoblotting assay of purified IgG anti-U1-RNP antibodies showed that these antibodies could bind to various membrane proteins of NP40-treated HPAECs such as 68, 48, 43, 38, 33, 29, 28 and 24 kDa. Some bands, 68, 33, 28 and 24 kDa, seemed to correspond to components of U1-RNP, i.e. 68 kDa, A, B' and C peptides, respectively. We confirmed that the anti-U1-RNP antibody from patients with CTDs can directly recognize a variety of antigens on the endothelial surface of the pulmonary artery, including the components of U1-RNP or other unknown polypeptides. These results suggest that binding to pulmonary artery endothelial cells of this autoantibody may be one of the triggers of endothelial cell inflammation in CTDs.
To develop a measurement of lupus disease activity over time.
We studied patients from the University of Toronto Lupus Clinic with "regular" followup, defined as having been in the clinic for at least 3 visits and never having been away from the clinic for a period exceeding 18 consecutive months. For each visit, disease activity was evaluated with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). The common approach to summarize over multiple visits by calculating a mean ignores the presence of varying time intervals between visits. We used the adjusted mean SLEDAI-2K (AMS), determined by the calculation of the area under the curve of SLEDAI-2K over time by adding the area of each of the blocks of visit interval and then dividing by the length of time for the whole period. The resulting AMS has the same units as the original SLEDAI-2K. A time-dependent covariate survival analysis was done to test which of AMS, SLEDAI-2K at presentation, sex, and age at diagnosis is the best predictor of mortality.
A total of 575 patients with regular followup were included. Only AMS and age at diagnosis were significant predictors. Odds ratio (OR) and 95% confidence intervals (CI) for AMS: OR 1.15 (CI 1.09, 1.20), p = 0.0001; age at diagnosis: OR 1.05 (CI 1.03, 1.06), p = 0.0001.
AMS represents an average disease activity measure over time and is strongly associated with mortality.
In the present study, we assessed the frequency and characteristics of the main causes of morbidity and mortality in systemic lupus erythematosus (SLE) during a 10-year period and compared the frequency of early manifestations with those that appeared later in the evolution of the disease. In 1990, we started a multicenter study of 1,000 patients from 7 European countries. All had medical histories documented and underwent medical interview and routine general physical examination when entered in the study, and all were followed prospectively by the same physicians during the ensuing 10 years (1990-2000).A total of 481 (48.1%) patients presented 1 or more episodes of arthritis at any time during the 10 years, 311 (31.1%) patients had malar rash, 279 (27.9%) active nephropathy, 194 (19.4%) neurologic involvement, 166 (16.6%) fever, 163 (16.3%) Raynaud phenomenon, 160 (16.0%) serositis (pleuritis and/or pericarditis), 134 (13.4%) thrombocytopenia, and 92 (9.2%) thrombosis. When the prevalences of the clinical manifestations during the initial 5 years of follow-up (1990-1995) were compared with those during the ensuing 5 years (1995-2000), most manifestations were found to be more frequent during the initial 5 years. Of the 1,000 patients, 360 (36%) presented infections, 169 (16.9%) hypertension, 121 (12.1%) osteoporosis, and 81 (8.1%) cytopenia due to immunosuppressive agents. Twenty-three (2.3%) patients developed malignancies; the most frequent primary localizations were the uterus and the breast.Sixty-eight (6.8%) patients died, and the most frequent causes of death were similarly divided between active SLE (26.5%), thromboses (26.5%), and infections (25%). A survival probability of 92% at 10 years was found. A lower survival probability was detected in those patients who presented at the beginning of the study with nephropathy (88% versus 94% in patients without nephropathy, p = 0.045). When the causes of death during the initial 5 years of follow-up (1990-1995) were compared with those during the ensuing 5 years (1995-2000), active SLE and infections (28.9% each) appeared to be the most common causes during the initial 5 years, while thromboses (26.1%) became the most common cause of death during the last 5 years.In conclusion, most of the SLE inflammatory manifestations appear to be less common after a long-term evolution of the disease, probably reflecting the effect of therapy as well as the progressive remission of the disease in many patients. Meanwhile, a more prominent role of thrombotic events is becoming evident, affecting both morbidity and mortality in SLE.
Venous thrombosis is a relatively frequent and serious complication in systemic lupus erythematosus (SLE) that has been associated with the presence of antiphospholipid antibodies (aPL). However, venous thrombotic events can also be seen in patients without aPL, and only a few patients with aPL develop venous thrombosis. This study was carried out to ascertain other factors contributing to the development of venous thrombosis in SLE.
Patients with SLE, ages > or = 16 years with < or = 5 years disease duration and of Hispanic, African American, or Caucasian ethnicity, from LUMINA (LUpus in MInorities, NAture versus nurture), a multiethnic, longitudinal study of outcome, were studied. Selected socioeconomic/demographic, clinical, laboratory, and treatment-exposure variables were compared between patients who developed and those who did not develop venous thrombotic events. Significant and clinically relevant variables were then entered into different multivariable models (Cox proportional hazards and unconditional stepwise logistic regression) to identify independent risk factors associated with the primary outcome. In another model, only patients who developed an event after enrollment (time 0) in the cohort were included.
Of 570 LUMINA patients, 51 developed at least 1 venous thrombotic event after SLE diagnosis. In univariable analyses, smoking (P = 0.020), shorter disease duration at time 0 (P = 0.017), serum levels of total cholesterol, low-density lipoprotein, and triglycerides (all P < 0.0001), and presence of lupus anticoagulant (LAC) (P = 0.045) were associated with venous thrombotic events. Survival analyses showed a time-dependent significant association of the primary outcome with smoking (P = 0.008) and a borderline significant association with the presence of LAC (P = 0.070). Multivariable models showed an independent association with smoking, age at time 0, disease activity over time, LAC, mean dose of glucocorticoids, and shorter disease duration at time 0.
Venous thrombotic events occur early in the course of SLE. Our data confirm the association between LAC and venous thrombotic events. Smoking, shorter disease duration, older age, disease activity over time, and higher mean daily glucocorticoid dose were identified as additional risk factors for the development of this vascular complication. These findings may have implications for the management of patients with SLE.
To compare the incidence and risk factors for thromboembolic events in systemic lupus erythematosus (SLE) patients of different ethnic backgrounds.
SLE patients who were newly diagnosed or were referred within 6 months of diagnosis between 1996 and 2002 were prospectively followed up for the occurrence of thromboembolic events. Cumulative hazard and risk factors for thromboembolism were evaluated and compared among patients of different ethnic origins.
We studied 625 patients who fulfilled the American College of Rheumatology criteria for SLE (89% women): 258 Chinese, 140 African Americans, and 227 Caucasians. The mean +/- SD age at SLE diagnosis was 35.7 +/- 14 years. After a followup of 3,094 patient-years, 48 arterial events and 40 venous events occurred in 83 patients. The overall incidence of arterial and venous thromboembolism was 16/1,000 patient-years and 13/1,000 patient-years, respectively. The cumulative hazard of arterial events at 60 months after the diagnosis of SLE was 8.5%, 8.1%, and 5.1% for the Chinese, African Americans, and Caucasians, respectively. The corresponding cumulative risk of venous events was 3.7%, 6.6%, and 10.3%, respectively (P = 0.008 for Chinese versus Caucasians, by log rank test). Smoking, obesity, antiphospholipid antibodies, and use of antimalarial agents and exogenous estrogens were less frequent in the Chinese patients. In Cox regression models, low levels of high-density lipoprotein (HDL) cholesterol, Chinese ethnicity, oral ulcers, and serositis predicted arterial events, whereas male sex, low levels of HDL cholesterol, antiphospholipid antibodies, non-Chinese ethnicity, obesity, renal disease, and hemolytic anemia predicted venous events.
There are ethnic differences in the incidence of arterial and venous thromboembolism in patients with SLE that cannot be fully explained by the clinical factors studied. Further evaluation of other genetic and immunologic factors is warranted.
Inflammation initiates clotting, decreases the activity of natural anticoagulant mechanisms and impairs the fibrinolytic system. Inflammatory cytokines are the major mediators involved in coagulation activation. The natural anticoagulants function to dampen elevation of cytokine levels. Furthermore, components of the natural anticoagulant cascades, like thrombomodulin, minimise endothelial cell dysfunction by rendering the cells less responsive to inflammatory mediators, facilitate the neutralisation of some inflammatory mediators and decrease loss of endothelial barrier function. Hence, downregulation of anticoagulant pathways not only promotes thrombosis but also amplifies the inflammatory process. When the inflammation-coagulation interactions overwhelm the natural defence systems, catastrophic events occur, such as manifested in severe sepsis or inflammatory bowel disease.
To examine autoantibody clusters and their associations with clinical features and organ damage accrual in patients with systemic lupus erythematosus (SLE).
The study group comprised 1,357 consecutive patients with SLE who were recruited to participate in a prospective longitudinal cohort study. In the cohort, 92.6% of the patients were women, the mean +/- SD age of the patients was 41.3 +/- 12.7 years, 55.9% were Caucasian, 39.1% were African American, and 5% were Asian. Seven autoantibodies (anti-double-stranded DNA [anti-dsDNA], anti-Sm, anti-Ro, anti-La, anti-RNP, lupus anticoagulant (LAC), and anticardiolipin antibody [aCL]) were selected for cluster analysis using the K-means cluster analysis procedure.
Three distinct autoantibody clusters were identified: cluster 1 (anti-Sm and anti-RNP), cluster 2 (anti-dsDNA, anti-Ro, and anti-La), and cluster 3 (anti-dsDNA, LAC, and aCL). Patients in cluster 1 (n = 451), when compared with patients in clusters 2 (n = 470) and 3 (n = 436), had the lowest incidence of proteinuria (39.7%), anemia (52.8%), lymphopenia (33.9%), and thrombocytopenia (13.7%). The incidence of nephrotic syndrome and leukopenia was also lower in cluster 1 than in cluster 2. Cluster 2 had the highest female-to-male ratio (22:1) and the greatest proportion of Asian patients. Among the 3 clusters, cluster 2 had significantly more patients presenting with secondary Sjögren's syndrome (15.7%). Cluster 3, when compared with the other 2 clusters, consisted of more Caucasian and fewer African American patients and was characterized by the highest incidence of arterial thrombosis (17.4%), venous thrombosis (25.7%), and livedo reticularis (31.4%). By using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, the greatest frequency of nephrotic syndrome (8.9%) was observed in patients in cluster 2, whereas cluster 3 patients had the highest percentage of damage due to cerebrovascular accident (12.8%) and venous thrombosis (7.8%). Osteoporotic fracture (11.9%) was also more common in cluster 3 than in cluster 2.
Autoantibody clustering is a valuable tool to differentiate between various subsets of SLE, allowing prediction of subsequent clinical course and organ damage.
Antibodies to beta2-glycoprotein I (anti-beta2-GPI) are found in a large percentage of patients with primary or secondary antiphospholipid syndrome (APS). Our aim was to identify the prevalence and clinical correlation of these antibodies in patients with APS and systemic lupus erythematosus (SLE), in comparison to anticardiolipin (aCL) and the lupus anticoagulant (LAC). We investigated whether serial samples improve clinical utility.
Serum samples for anti-beta2-GPI (IgG, IgM, IgA), aCL (IgG, IgM, IgA), and LAC (by dilute Russell viper venom time; RVVT) were collected from 418 consecutive patients with SLE or APS between October 2002 and March 2003. Clinical and serologic data of these patients were analyzed.
A total of 185 (44.5%) patients were positive for anti-beta2-GPI, 55.3% were positive for aCL, and 31.1% for LAC. Anti-beta2-GPI was more common in Caucasians than in African Americans (p = 0.098). IgM and IgA were the most frequent isotypes of anti-beta2-GPI. aCL and anti-beta2-GPI were highly associated (p < 0.0001 to p = 0.0177, depending on isotype). A positive association was found between the presence of the LAC by dilute RVVT and anti-beta2-GPI IgG (p < 0.0001), IgM (p < 0.0001), and IgA (p = 0.0002) antibodies. Persistent positivity increased the association of venous and arterial thrombosis with anti-beta2-GPI (IgG and IgM isotypes). Pregnancy loss, seizures, and migraines were not associated with anti-beta2-GPI. IgA anti-beta2-GPI was not significantly associated with any manifestation of APS.
The prevalence of anti-beta2-GPI IgM and IgA was very high in our population. Measurement of anti-beta2-GPI IgG is clinically useful in identifying patients with SLE at higher risk for venous and arterial thrombosis. Persistent positivity increased the association of IgG anti-beta2-GPI with venous thrombosis and anti-beta2-GPI IgM with arterial thrombosis. IgA anti-beta2-GPI was not significantly associated with APS manifestations.
Certain autoantibodies are characteristic of autoimmune disease manifestations and contribute to organ pathology. The presence of high-titer antibodies to U1-RNP are associated with mixed connective tissue disease, although these antibodies may also be present in systemic lupus erythematosus and systemic sclerosis. However, the role of antibodies to U1-RNP in the pathogenesis of connective tissue disease remains unclear. Data from recent experimental studies promote the hypothesis that U1-RNP antibodies participate in both innate and adaptive immune responses, implicating them in the pathogenesis of connective tissue disease.
The 1982 American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus
- E M Tan
- A S Cohen
- J F Fries
- A T Masi
- D J Mcshane
- N F Rothfield
- EM Tan
The interaction between inflammation and coagulation
- C T Esmon
Esmon CT (2005) The interaction between inflammation and coagulation. Br J Haematol 131:417-430