Impaired Microcirculation and Vascular Hemodynamics in Relation to Macrocirculation in Patients With Systemic Lupus Erythematosus

Introduction: Systemic lupus erythematosus (SLE) is associated with premature cardiovascular disease (CVD) and mortality, unexplained by traditional risk factors. Impairment of microcirculation and vascular hemodynamics may represent early signs of vascular affection. We hypothesized that studies of microcirculation and pulse waves may provide additional information, compared to ultrasound (US) alone, for the detection of early vascular disease in SLE.Methods: Sixty well-characterized SLE-patients (52 women, eight men; mean age 43.21 ± 1.3 years) characterized by lupus nephritis (LN; n = 20), antiphospholipid syndrome (APS; n = 20) or skin and joint involvement (n = 20) and 60 healthy controls were included. Microcirculatory peak oxygen saturation (OxyP) was evaluated using a novel combined laser Doppler flowmetry/diffuse reflectance spectroscopy method. Pulse waves were recorded in the radial artery by the aid of applanation tonometry in order to calculate central augmentation index (AIx75). Intima-media thickness (IMT) and plaque occurrence were evaluated using high frequency US, in carotid and central arteries.Results: Lower OxyP (84 ± 8 vs. 87 ± 5 %, p = 0.01) and higher AIx75 (17.3 ± 13.9 vs. 10.0 ± 14.2 %, p = 0.005) were seen in the SLE cohort. OxyP was inversely correlated with IMT in internal carotid artery (ICA), (R = −0.32, p = 0.01). AIx75 correlated with IMT in common carotid artery (CCA), (R = 0.36, p = 0.005), common femoral artery (CFA), (R = 0.43, p = 0.001), and ICA (R = 0.27, p = 0.04). AIx75 correlated negatively with OxyP (R = −0.29, p = 0.02). SLE-patients with plaque had lower OxyP values (80 ± 8 vs. 85 ± 7 %, p < 0.001) and higher AIx75 (23.0 ± 11.6 vs. 15.5 ± 14.2 %, p < 0.001) compared to those without plaque.Conclusion: Impaired microcirculation and vessel hemodynamics were observed in SLE. These methods correlated with IMT and plaque occurrence. The importance of early macro- and micro-circulatory vascular affection for increased risk of CVD in SLE will be followed-up in future studies.

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Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus

Nature Communications ◽

10.1038/s41467-021-23361-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sarfaraz A. Hasni ◽

Sarthak Gupta ◽

Michael Davis ◽

Elaine Poncio ◽

Yenealem Temesgen-Oyelakin ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Kinase Inhibitor ◽

Janus Kinase ◽

Controlled Clinical Trial ◽

Type I ◽

Systemic Lupus ◽

Double Blind ◽

Premature Cardiovascular Disease ◽

Increased Risk

AbstractIncreased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity (p = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.

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Systemic lupus erythematosus and the risk of cardiovascular disease

Practical management of the pregnant patient with rheumatic disease ◽

10.1093/med/9780198845096.003.0014 ◽

2021 ◽

pp. 162-164

Author(s):

Karen Schreiber ◽

Søren Jacobsen

Keyword(s):

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

Patient Group ◽

Lupus Erythematosus ◽

Childbearing Age ◽

Systemic Lupus ◽

Previous Pregnancy ◽

Premature Cardiovascular Disease ◽

Increased Risk ◽

History Of

Women account for roughly 90% of patients with systemic lupus erythematosus (SLE) and they are typically diagnosed when they are in their childbearing age. Patients with SLE are at increased risk of premature cardiovascular disease (CVD) representing the major cause of morbidity and mortality in this patient group. Premature CVD is significantly pronounced in women with SLE who have a history of pre-eclampsia compared to those who have no history of pre-eclampsia. Therefore, the prevention of future CVD is particularly important in women with a previous pregnancy history complicated by pre-eclampsia. Patients worry about the possible risk for future CVD.

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Systemic lupus erythematosus

Practical management of the pregnant patient with rheumatic disease ◽

10.1093/med/9780198845096.003.0013 ◽

2021 ◽

pp. 157-161

Author(s):

Karen Schreiber ◽

Monika Østensen

Keyword(s):

Systemic Lupus Erythematosus ◽

Cardiovascular Disease ◽

Patient Group ◽

Lupus Erythematosus ◽

Childbearing Age ◽

Systemic Lupus ◽

Previous Pregnancy ◽

Premature Cardiovascular Disease ◽

Increased Risk ◽

History Of

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Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-204837 ◽

2014 ◽

Vol 74 (7) ◽

pp. 1417-1424 ◽

Cited By ~ 167

Author(s):

Carmelo Carmona-Rivera ◽

Wenpu Zhao ◽

Srilakshmi Yalavarthi ◽

Mariana J Kaplan

Keyword(s):

Systemic Lupus Erythematosus ◽

Endothelial Dysfunction ◽

Lupus Erythematosus ◽

Endothelial Damage ◽

Neutrophil Extracellular Trap ◽

Matrix Metalloproteinase 2 ◽

Systemic Lupus ◽

Functional Integrity ◽

Premature Cardiovascular Disease ◽

Increased Risk

RationaleThe 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.ObjectiveTo determine the mechanism by which enhanced NET formation by low-density granulocytes (LDGs) in SLE contributes to endothelial damage and disrupts the endothelium.ResultsThe 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.ConclusionsThese 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.

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Risk of osteonecrosis in systemic lupus erythematosus: An 11-year Chinese single-center cohort study

Lupus ◽

10.1177/09612033211021166 ◽

2021 ◽

pp. 096120332110211

Author(s):

Yin Long ◽

Shangzhu Zhang ◽

Jiuliang Zhao ◽

Hanxiao You ◽

Li Zhang ◽

...

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Risk Factor ◽

Femoral Head ◽

Lupus Erythematosus ◽

Femoral Head Necrosis ◽

Joint Involvement ◽

Multiple Site ◽

Systemic Lupus ◽

Cns Involvement

Objective Osteonecrosis (ON), which can lead to physical disability, is a common complication of systemic lupus erythematosus (SLE). The purpose of this study was to determine the prevalence of ON and identify possible risk factors in Chinese SLE patients. Methods SLE patients who fulfilled the 1997 American College of Rheumatology SLE classification criteria were recruited from the Peking Union Medical College Hospital. The chi-square test (χ 2 test) and multivariate regression analyses were used to evaluate risk factors. The Cox proportional-hazards model was used to construct the survival curves and estimate the simultaneous effects of prognostic factors on survival. Results We consecutively enrolled 1,158 patients, of which 88 patients (7.6%) developed ON. Among ON patients, 57.1% of patients had isolated femoral head necrosis and 42.9% had multiple joint involvement. The mean age of ON patients (24.62 ± 8.89 years) was significantly younger than SLE patients without ON (27.23 ± 10.16 years, p = 0.09). The ON group presented with a much longer disease course (10.68 ± 5.97 years, p < 0.001) and increased incidence of arthritis, kidney, and central nervous system (CNS) involvement (65.9% [ p < 0.05], 57.6% [ p < 0.05], and 16.5% [ p < 0.05], respectively, in the ON group). ON patients were more likely to be treated with glucocorticoid (GC) and to receive a high dose of prednisolone at the initial stage of SLE ( p < 0.05). The percentage of patients who received hydroxychloroquine was much higher in the control group ( p < 0.001). Cox regression analysis suggested that CNS involvement and GC therapy were two independent risk factors for ON in SLE patients. The presence of anti-phospholipid antibodies (aPLs) was a risk factor for multiple joint necrosis (odds ratio: 6.28, p = 0.009). Conclusions ON remains a serious and irreversible complication in SLE. In addition to glucocorticoid therapy, we found that CNS system involvement was a risk factor for ON, while the administration of hydroxychloroquine was a protective factor. The clinical characteristics of multiple site ON patients were distinct from isolated femoral head necrosis patients. The presence of aPLs was a risk factor for multiple site osteonecrosis.

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POS0685 MYCOPHENOLATE MOFETIL IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS: FIVE-YEARS DRUG SURVIVAL IN RENAL AND NON-RENAL INVOLVEMENT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.925 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 588.2-588

Author(s):

G. Olivieri ◽

F. Ceccarelli ◽

F. Natalucci ◽

F. R. Spinelli ◽

C. Alessandri ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Mycophenolate Mofetil ◽

Disease Activity ◽

Lupus Erythematosus ◽

Treatment Duration ◽

Retention Rate ◽

Renal Involvement ◽

Joint Involvement ◽

Systemic Lupus ◽

Median Treatment

Background:The updated EULAR recommendations for the management of systemic lupus erythematosus (SLE) underline the use of Mycophenolate Mofetil (MMF) in the treatment of different disease related manifestations (1). Several randomized controlled trials have demonstrated the efficacy of MMF in lupus nephritis (LN) patients but only case series and open-labelled trials have analyzed the use of this drug in other than LN features. Moreover, no data are available about the MMF retention rate in a real-life setting.Objectives:The present study aims at evaluating the 5-years drug retention rate (DRR) of MMF in a large monocentric SLE cohort. Secondly, we investigated the influence of MMF in disease activity changes and chronic damage progression.Methods:We performed a longitudinal study including all the SLE patients (ACR 1997 criteria) starting MMF treatment in our Lupus Clinic. Data about indications, mean dosage, duration of treatment and reasons for drug withdrawal were registered. The DRR was estimated using the Kaplan–Meier method. Disease activity and chronic damage were assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SLICC Damage Index (SDI), respectively.Results:The present analysis included 162 SLE patients (M/F 22/140, median age at the disease diagnosis 25.5 years, IQR 13). At the beginning of MMF treatment, we registered a median age of 34 months (IQR 21) and a median disease duration of 72 months (IQR 123). The most frequent indications for prescribing MMF were LN (101 patients, 62.3%) and musculoskeletal manifestations (39, 24.1%), followed by neuropsychiatric involvement (10, 6.2%), and others disease related manifestations (12, 7.4%; in particular skin involvement, hematological features, myositis, vasculitis). MMF was administered at a mean daily dosage of 2.1±0.6 grams; no differences in dosage were found between the different indications (p=ns).At the longitudinal analysis, we registered a median treatment duration of 30 months (IQR 55). Figure 1 reported data about DRR: in particular, at 60 months follow-up we observed a DRR of 61.1% for LN patients, which was similar to that registered for patients without renal involvement (NLN) (60.5%; p=ns). Interestingly, the DRR at 60 months was higher in the subgroup of patients treated for joint involvement (75.4%), even without reaching a statistically significant difference. During the observation period, 92 patients (59.2%) discontinued MMF (median treatment duration at discontinuation 25 months, IQR 35). Interestingly, the main cause of withdrawal was the achievement of persistent remission, observed in 20 patients (21.7%), followed by loss of efficacy (19 patients, 20.5%), drug intolerance and pregnancy planning (17 patients for both reasons, 18,4%). Furthermore, our analysis confirmed MMF efficacy, as demonstrated by the significant reduction in SLEDAI-2k values after 4, 12 and 24 months of treatment (p< 0.0001 for all the time-points in comparison with baseline). In addition, MMF resulted able to control chronic damage progression, as demonstrated by the lack of significant increase in SDI values (baseline: 0.6, IQR 1; last observation: 0.93, IQR 1; p=ns).Conclusion:The evaluation of a large SLE cohort demonstrated a good retention rate for MMF. In particular, our results demonstrated that MMF is also a safe and effective drug for SLE manifestation other than LN, in particular for joint involvement. Moreover, it is able to control disease activity and to prevent the progression of chronic damage.References:[1]Fanouriakis A et al. Ann Rheum Dis. 2019 Jun;78(6):736-745.Disclosure of Interests:None declared

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Symptomatic osteonecrosis of the hip and knee in patients with systemic lupus erythematosus: Prevalence, pattern, and comparison of natural course

Lupus ◽

10.1177/09612033211031007 ◽

2021 ◽

pp. 096120332110310

Author(s):

Mehmet Ersin ◽

Mehmet Demirel ◽

Mehmet Ekinci ◽

Lezgin Mert ◽

Çiğdem Çetin ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Rheumatic Diseases ◽

Lupus Erythematosus ◽

Bone Structure ◽

Survival Rates ◽

Knee Joints ◽

Joint Involvement ◽

Systemic Lupus ◽

Kaplan Meier ◽

The Mean

Objective Osteonecrosis (ON), also known as avascular necrosis, is characterized by the collapse of the architectural bone structure secondary to the death of the bone marrow and trabecular bone. Osteonecrosis may accompany many conditions, especially rheumatic diseases. Among rheumatic diseases, osteonecrosis is most commonly associated with systemic lupus erythematosus (SLE). We assessed prevalence and distribution pattern of symptomatic ON in patients with SLE and compare the natural courses of hip and knee ON. Methods 912 SLE patients admitted between 1981 and 2012 were reviewed. SLE patients with symptomatic ON were retrospectively identified both from the existing SLE/APS database. The prevalence of symptomatic ON was calculated; with ON, the joint involvement pattern was determined by examining the distribution of the joints involved, and then the data about the hip and knee joints were entered in the Kaplan-Meier analysis. Kaplan-Meier methods were used to calculate 5- and 10-year rates of ON-related hip (the hip group) and knee survival (the knee group). Results Symptomatic ON developed in various joints in 97 of 912 patients with SLE, and the overall prevalence of ON was detected as 10.6%. The mean age at the time of SLE and ON diagnoses were 27.9 ± 9.9 (14–53) and 34.2 ± 11.3 (16–62) years, respectively. The mean duration from diagnosis of SLE to the first development of ON was 70.7± 60.2 (range = 0–216) months. The most common site for symptomatic ON was the hips (68%, n=66), followed by the knees (38%, n = 37). According to Kaplan-Meier analysis, hip and knee joint survival rates associated with 5-year ON were 51% and 88%, and 10-year survival rates were 43% and 84%, respectively. Conclusion We observed that the prevalence of symptomatic ON in patients with SLE was 10.6%. With the estimated 10-year survival rates of 40% versus 84% for the hip and knee joints, respectively, hip involvement may demonstrate a more aggressive course to end-stage osteoarthritis than the knee involvement.

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Imaging of Joint and Soft Tissue Involvement in Systemic Lupus Erythematosus

Current Rheumatology Reports ◽

10.1007/s11926-021-01040-8 ◽

2021 ◽

Vol 23 (9) ◽

Author(s):

Andrea Di Matteo ◽

Gianluca Smerilli ◽

Edoardo Cipolletta ◽

Fausto Salaffi ◽

Rossella De Angelis ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Soft Tissue ◽

Lupus Erythematosus ◽

Structural Damage ◽

Structural Changes ◽

Soft Tissues ◽

Imaging Techniques ◽

Joint Involvement ◽

Systemic Lupus ◽

Muscle Involvement

Abstract Purpose of Review To highlight the potential uses and applications of imaging in the assessment of the most common and relevant musculoskeletal (MSK) manifestations in systemic lupus erythematosus (SLE). Recent Findings Ultrasound (US) and magnetic resonance imaging (MRI) are accurate and sensitive in the assessment of inflammation and structural damage at the joint and soft tissue structures in patients with SLE. The US is particularly helpful for the detection of joint and/or tendon inflammation in patients with arthralgia but without clinical synovitis, and for the early identification of bone erosions. MRI plays a key role in the early diagnosis of osteonecrosis and in the assessment of muscle involvement (i.e., myositis and myopathy). Conventional radiography (CR) remains the traditional gold standard for the evaluation of structural damage in patients with joint involvement, and for the study of bone pathology. The diagnostic value of CR is affected by the poor sensitivity in demonstrating early structural changes at joint and soft tissue level. Computed tomography allows a detailed evaluation of bone damage. However, the inability to distinguish different soft tissues and the need for ionizing radiation limit its use to selected clinical circumstances. Nuclear imaging techniques are valuable resources in patients with suspected bone infection (i.e., osteomyelitis), especially when MRI is contraindicated. Finally, dual energy X-ray absorptiometry represents the imaging mainstay for the assessment and monitoring of bone status in patients with or at-risk of osteoporosis. Summary Imaging provides relevant and valuable information in the assessment of MSK involvement in SLE.

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Comparison of risk factors for vascular disease in the carotid artery and aorta in women with systemic lupus erythematosus

Arthritis & Rheumatism ◽

10.1002/art.11418 ◽

2004 ◽

Vol 50 (1) ◽

pp. 151-159 ◽

Cited By ~ 148

Author(s):

Faith Selzer ◽

Kim Sutton-Tyrrell ◽

Shirley G. Fitzgerald ◽

Joan E. Pratt ◽

Russell P. Tracy ◽

...

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Carotid Artery ◽

Vascular Disease ◽

Lupus Erythematosus ◽

Systemic Lupus

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European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-219373 ◽

2021 ◽

pp. annrheumdis-2020-219373

Author(s):

Martin Aringer ◽

Ralph Brinks ◽

Thomas Dörner ◽

David Daikh ◽

Marta Mosca ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Metabolic Diseases ◽

Classification Criteria ◽

Joint Involvement ◽

Systemic Lupus ◽

Entry Criterion ◽

American College Of Rheumatology ◽

European League Against Rheumatism ◽

European League

Background/objectivesThe European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria.MethodsWe combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE.ResultsPositive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement.ConclusionsChanging the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

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