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1.
Lupus Sci Med ; 8(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33479047

RESUMO

BACKGROUND AND AIMS: We hypothesised that intracellular homocysteine and homocysteine metabolite levels in patients with SLE are disproportionately elevated compared with the levels seen in healthy subjects and that they are independently associated with coronary plaque in SLE. METHODS: A liquid chromatography-tandem mass spectrometry absolute quantification assay was used for the determination of six analytes in both plasma and peripheral blood mononuclear cells (PBMCs): homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), methionine (Met), cystathionine (Cysta) and 5-methyltetrahydrofolate (5m-THF). We then compared intracellular (PBMC) and extracellular (plasma) Hcy and Hcy metabolite (SAM, SAH, Met, Cysta and 5m-THF) concentrations in 10 patients with SLE and in 10 age, sex and ethnicity matched controls. Subjects with a history of diabetes mellitus, cardiovascular disease, hypertension, alcohol consumption in excess of 3 units per day, anaemia, renal insufficiency (serum creatinine >1.5 mg/dL) and pregnancy were excluded. All patients with SLE had two coronary CT angiography studies as screening for occult coronary atherosclerotic disease. RESULTS: Plasma from patients with SLE had higher levels of Hcy (p<0.0001), SAH (p<0.05), SAM (p<0.001) and lower levels of Met (p<0.05) and Cysta (p<0.001) compared with controls. PBMC intracellular concentrations from patients with SLE had higher levels of Cysta (p<0.05), SAH (p<0.05), SAM (p<0.001) and lower levels of 5m-THF (p<0.001). Plasma SAH showed a positive correlation with total coronary plaque, calcified plaque and non-calcified plaque (p<0.05). CONCLUSION: Intracellular concentrations of Hcy metabolites were significantly different between patients with SLE and controls, despite similar intracellular Hcy levels. Plasma SAH was positively correlated with total coronary plaque, calcified plaque and non-calcified plaque.

2.
Lupus Sci Med ; 7(1)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33139453

RESUMO

OBJECTIVE: Persistent positivity for lupus anticoagulant has been associated with an increased risk of thrombosis among patients with SLE. Persistent positivity is often defined as having two positive assessments separated by more than 90 days. Our objective was to determine whether frequent repeated lupus anticoagulant testing would identify more patients with persistent positivity, and whether the additional patients identified were still at increased risk of thrombosis. METHODS: Using a large longitudinal cohort with frequent lupus anticoagulant testing, we compared three different hypothetical clinical strategies for identifying persistent positivity: (1) assessment of lupus anticoagulant twice more than 90 days apart; (2) assessment of lupus anticoagulant annually, with repeat testing if an annual assessment was positive; and (3) assessment of lupus anticoagulant 16 times (approximately quarterly for 4 years). The prevalence of persistent positivity was compared between the approaches and by demographic subgroups. Subgroups based on these definitions were compared with respect to the risk of thrombosis in subsequent follow-up using discrete survival analysis. RESULTS: Among the 785 patients included in our analysis, the prevalence of persistent lupus anticoagulant as defined by the first two patient assessments was 4.3%. Annual assessment resulted in a prevalence of 6.6%, and using all 16 assessments resulted in a prevalence of 10.5%. The prevalence was substantially higher in men than in women, and in Caucasians than in African-Americans (p<0.01 for all comparisons). The rate of thrombosis was significantly elevated among those with persistently positive lupus anticoagulant by any definition (HR ranging from 2.75 to 3.42) relative to those without persistently positive lupus anticoagulant. CONCLUSION: While there are other risk factors for thrombosis (including other antiphospholipid subtypes), more frequent testing (not limited to twice over 3 months) for lupus anticoagulant would be useful for identifying more patients with SLE at elevated risk for thrombosis.

3.
Lupus Sci Med ; 7(1)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33037080

RESUMO

OBJECTIVE: To characterise the molecular pathways impacted by the pharmacologic effects of the Janus kinase (JAK) 1 and JAK2 inhibitor baricitinib in SLE. METHODS: In a phase II, 24-week, randomised, placebo-controlled, double-blind study (JAHH), RNA was isolated from whole blood in 274 patients and analysed using Affymetrix HTA2.0 array. Serum cytokines were measured using ultrasensitive quantitative assays. RESULTS: Gene expression profiling demonstrated an elevation of STAT1, STAT2 and multiple interferon (IFN) responsive genes at baseline in patients with SLE. Statistical and gene network analyses demonstrated that baricitinib treatment reduced the mRNA expression of functionally interconnected genes involved in SLE including STAT1-target, STAT2-target and STAT4-target genes and multiple IFN responsive genes. At baseline, serum cytokines IFN-α, IFN-γ, interleukin (IL)-12p40 and IL-6 were measurable and elevated above healthy controls. Treatment with baricitinib significantly decreased serum IL-12p40 and IL-6 cytokine levels at week 12, which persisted through week 24. CONCLUSION: Baricitinib treatment induced significant reduction in the RNA expression of a network of genes associated with the JAK/STAT pathway, cytokine signalling and SLE pathogenesis. Baricitinib consistently reduced serum levels of two key cytokines implicated in SLE pathogenesis, IL-12p40 and IL-6.

4.
Lupus Sci Med ; 7(1)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33023978

RESUMO

BACKGROUND/PURPOSE: Loss of positivity of antiphospholipid antibodies has been observed in clinical practice post-thrombosis in patients with SLE with secondary antiphospholipid syndrome (APS). Our study defined the frequency of this loss and the duration before positivity recurred. METHODS: In this prospective study, patients with SLE having at least two positive antiphospholipid markers prior to thrombosis and at least 1 year of follow-up after thrombosis were included. Antiphospholipid markers included lupus anticoagulant (dilute Russell viper venom test >45 s followed by mixing and confirmatory tests) and/or anticardiolipin titre (aCL IgG ≥20, aCL IgM ≥20 and/or aCL IgA ≥20). The percentage of visits with positive antiphospholipid markers after thrombosis was calculated. For patients with a negative antiphospholipid marker any time after thrombosis, survival estimates were performed to calculate the time to return of antiphospholipid positivity. RESULTS: In APS due to SLE, complete loss of antiphospholipid positivity post-thrombosis was up to 41% for aCL IgG, 51% for IgM and 50% for IgA, but only 20% for those with lupus anticoagulant. Of those who at some point lost aCL IgG or became negative for lupus anticoagulant, the majority (60% and 76%, respectively) reacquired the antibody within 5 years. In contrast, of those who lost aCL IgM or IgA, fewer reacquired it within 5 years (37% and 17%, respectively). CONCLUSION: Intermittent positivity of antiphospholipid antibodies is present in APS due to SLE. These fluctuations make it difficult to decide on length of anticoagulation. Lupus anticoagulant is more likely to persist post-thrombosis.

5.
Lupus Sci Med ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32963114

RESUMO

OBJECTIVES: We determined the temporal association between clinical and serological disease manifestations and development of cutaneous small vessel vasculitis in a large prospective multiethnic cohort. METHODS: Patients with SLE diagnosed according to the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria or the revised classification criteria as defined by the American College of Rheumatology (ACR) were enrolled in the Hopkins Lupus Cohort. Cutaneous small vessel vasculitis was determined as a component of the Systemic Lupus Erythematosus Disease Activity Index. SLE-associated cutaneous small vessel vasculitis lesions were reported clinically. They presented as punctate lesions, palpable purpura, tender erythematous plaques or macules with or without necrosis. No histopathological diagnosis was pursued to confirm the diagnosis of vasculitis or to differentiate it from other causes of digital lesions in patients with SLE. Disease manifestations that preceded the first occurrence of cutaneous small vessel vasculitis lesions were analysed using Kaplan-Meier. Cox regression analysis was used to assess the relationship between baseline clinical and immunological manifestations and the development of cutaneous small vessel vasculitis. We adjusted for gender, race and age at SLE diagnosis. RESULTS: A total of 2580 patients were studied: 52.4% were Caucasian and 39.4% were African-American. The mean age of the cohort was 45.5±14.5 years. The mean years of cohort follow-up was 7.9±7.6. Cutaneous small vessel vasculitis was observed in 449 (17.3%). The mean time to cutaneous vasculitis after SLE diagnosis was 4.78 years (95% CI 3.96 to 5.60). At least 159 (35%) patients had recurrences of cutaneous vasculitis lesions. Discoid rash, Raynaud's phenomenon, myositis, anaemia, Coombs' positivity, leucopenia, anti-Smith and anti-RNP (Ribonucleoprotein) were significantly associated with the development of cutaneous vasculitis. The SLICC/ACR Damage Index score was higher in patients with cutaneous vasculitis compared with those without cutaneous vasculitis. CONCLUSIONS: Cutaneous vasculitis is frequent (17.3%) and often recurrent (35%). African-Americans are at higher risk of developing cutaneous small vessel vasculitis than Caucasians. Clinical presentations such as myositis and haematological manifestations are predictors of cutaneous vasculitis development. The presence of cutaneous vasculitis is associated with increased organ damage.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32813314

RESUMO

OBJECTIVE: To assess cancer risk factors in incident SLE. METHODS: Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (over-all risk, and most common cancers) included demographics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and adjusted mean SLE Disease Activity Index-2K. RESULTS: Among 1668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 non-melanoma skin, seven lung, six hematological, six prostate, five melanoma, three cervical, three renal, two each gastric, head and neck, and thyroid, and one each rectal, sarcoma, thymoma, and uterine cancers. Half of cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated over-all cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively and anti-malarial drugs were negatively associated. Anti-malarial drugs and higher disease activity were also negatively associated with non-melanoma skin cancer (NMSC) risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with NMSC risk. CONCLUSIONS: Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and NMSC. Antimalarials were negatively associated with breast cancer and NMSC risk. SLE activity was associated positively with hematologic cancer and negatively with NMSC. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings.

7.
JCI Insight ; 5(15)2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32759501

RESUMO

Gene expression signatures can stratify patients with heterogeneous diseases, such as systemic lupus erythematosus (SLE), yet understanding the contributions of ancestral background to this heterogeneity is not well understood. We hypothesized that ancestry would significantly influence gene expression signatures and measured 34 gene modules in 1566 SLE patients of African ancestry (AA), European ancestry (EA), or Native American ancestry (NAA). Healthy subject ancestry-specific gene expression provided the transcriptomic background upon which the SLE patient signatures were built. Although standard therapy affected every gene signature and significantly increased myeloid cell signatures, logistic regression analysis determined that ancestral background significantly changed 23 of 34 gene signatures. Additionally, the strongest association to gene expression changes was found with autoantibodies, and this also had etiology in ancestry: the AA predisposition to have both RNP and dsDNA autoantibodies compared with EA predisposition to have only anti-dsDNA. A machine learning approach was used to determine a gene signature characteristic to distinguish AA SLE and was most influenced by genes characteristic of the perturbed B cell axis in AA SLE patients.

8.
Lupus Sci Med ; 7(1)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32723810

RESUMO

BACKGROUND: Positive remodelling index and presence of low-attenuation non-calcified plaque (LANCP) are characteristic vessel changes in unstable coronary plaques. We sought to characterise these high-risk plaque features in patients with systemic lupus erythematosus (SLE) and to compare them with controls. METHODS: A total of 72 patients who satisfied the SLICC classification criteria for SLE had coronary CT angiography (CCTA) studies, 30 of which had follow-up CCTA, as screening for occult coronary atherosclerotic disease in asymptomatic individuals. A total of 100 consecutive controls with no known history of lupus, heart disease or revascularisation who had two coronary CT angiograms at least 1 year apart were included in the study. These were asymptomatic patients referred by their primary physicians for screening of coronary artery disease and the screening interval was decided by the primary physicians. The methodology for image acquisition was identical. RESULTS: LANCP burden at baseline was significantly greater in patients with SLE compared with controls. LANCP volume was significantly greater in patients over 60 years of age (p<0.05) and in those with current prednisone dose >10 mg/day. LANCP burden remained stable over follow-up. There were no significant differences in remodelling index compared with controls. CONCLUSION: This is the first study describing high-risk CCTA features of coronary plaque in patients with SLE. Both LANCP and positive remodelling are common in SLE. These characteristic vessel changes may identify patients with SLE at increased risk of cardiovascular events and those in need for more frequent cardiac monitoring.

9.
Lupus Sci Med ; 7(1)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32665303

RESUMO

OBJECTIVE: ß-1,4 galactosyltransferase-V (ß-1,4 GalT-V) is an enzyme that synthesises a glycosphingolipid known as lactosylceramide, which has been implicated in general inflammation and atherosclerosis. We asked if ß-1,4 GalT-V was present at elevated levels in patients with SLE, a disease which is associated with increased risk of atherosclerosis. METHODS: In this case-control observational study, serum samples were obtained from patients with SLE who are part of the Johns Hopkins Lupus Cohort. Control serum samples were obtained from healthy adult community members recruited from the Baltimore area. All serum samples (n=50 in the SLE group and n=50 in the healthy control group) were analysed with enzyme-linked immunoassays. These assays used antibodies raised against antigens that enabled us to measure the absorbance of oxidised phosphocholines per apolipoprotein B-100 (ox-PC/apoB) and the concentration of lipoprotein(a) (Lp(a)) and ß-1,4 GalT-V. RESULTS: Absorbance of ox-PC/apoB and concentrations of Lp(a) and ß-1,4 GalT-V were significantly higher in the SLE serum samples as compared with the control serum (p<0.0001). CONCLUSIONS: We conclude that patients with SLE have elevated levels of ß-1,4 GalT-V and ox-PC, which have previously been recognised as risk factors for atherosclerosis.

10.
Arthritis Rheumatol ; 72(10): 1734-1740, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32515554

RESUMO

OBJECTIVE: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE. METHODS: A large 33-center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient-years, and univariable and multivariable relative risk regression models. RESULTS: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow-up visit after enrollment, for a total of 13,666 patient-years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient-years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32-0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55-10.30]) and a body mass index of >40 kg/m2 (HR 2.74 [95% CI 1.04-7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17-9.27], P < 0.001). CONCLUSION: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors.

11.
J Immunol ; 204(5): 1334-1344, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953354

RESUMO

The IL1A and IL1B genes lie in close proximity on chromosome 2 near the gene for their natural inhibitor, IL1RN Despite diverse functions, they are all three inducible through TLR4 signaling but with distinct kinetics. This study analyzed transcriptional induction kinetics, chromosome looping, and enhancer RNA production to understand the distinct regulation of these three genes in human cells. IL1A, IL1B, and IL1RN were rapidly induced after stimulation with LPS; however, IL1B mRNA production was less inhibitable by iBET151, suggesting it does not use pause-release regulation. Surprisingly, chromatin looping contacts between IL1A and IL1B were highly intermingled, although those of IL1RN were distinct, and we focused on comparing IL1A and IL1B transcriptional pathways. Our studies demonstrated that enhancer RNAs were produced from a subset of the regulatory regions, that they were critical for production of the mRNAs, and that they bound a diverse array of RNA binding proteins, including p300 but not CBP. We, furthermore, demonstrated that recruitment of p300 was dependent on MAPKs. Integrator is another RNA binding protein recruited to the promoters and enhancers, and its recruitment was more dependent on NF-κB than MAPKs. We found that integrator and NELF, an RNA polymerase II pausing protein, were associated with RNA in a manner that facilitated interaction. We conclude that IL1A and IL1B share many regulatory contacts, signaling pathways, and interactions with enhancer RNAs. A complex of protein interactions with enhancer RNAs emphasize the role of enhancer RNAs and the overall structural aspects of transcriptional regulation.


Assuntos
Proteína p300 Associada a E1A/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Proteínas de Ligação a RNA/imunologia , Transcrição Genética , Linhagem Celular , Proteína p300 Associada a E1A/genética , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Proteínas de Ligação a RNA/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/imunologia
12.
Lupus Sci Med ; 6(1): e000346, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749976

RESUMO

Objective: Accelerated atherosclerosis remains the major cause of late death (after 5 years) in SLE. Yet, the 'traditional' cardiovascular risk equations (such as Framingham) consistently underestimate the risk. We sought to construct a data-driven formula for cardiovascular risk in SLE, based on data collected during the first year in a longitudinal cohort, for research purposes. Methods: Two risk formulas were derived: one was for a broad set of cardiovascular outcomes (myocardial infarction, stroke, onset of angina, coronary procedures such as bypass or stent, claudication, peripheral artery disease or congestive heart failure); and the other for hard outcomes (myocardial infarction or stroke). Traditional and SLE-specific risk factors for cardiovascular disease were measured during the first year of cohort participation. Using Cox proportional hazards modelling, SLE formulas to calculate the 10-year risk of a subsequent cardiovascular event were derived and compared with the Framingham (for the broader outcome) and American College of Cardiology formulas (for the hard outcomes). Results: SLE-related risk factors for each model included mean disease activity score (as measured by the SELENA revision of the SLE Disease Activity Index), low C3 and history of lupus anticoagulant. In those with SLE-related risk factors, the estimated 10-year risk based on our formula was substantially higher than the risk estimated based on the formulas for the general population. Conclusions: The excess cardiovascular risk among patients with SLE varies substantially depending on the SLE-related risk factors, age and traditional risk factors. Cardiovascular risk formulas based on individual data from patients with SLE may better estimate 10-year cardiovascular risk among patients with SLE than the Framingham or American College of Cardiology equations.

13.
Sci Rep ; 9(1): 14433, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594956

RESUMO

Systemic lupus erythematosus (SLE) impacts multiple organ systems, although the causes of many individual SLE pathologies are poorly understood. This study was designed to elucidate organ-specific inflammation by identifying proteins that correlate with SLE organ involvement and to evaluate established biomarkers of disease activity across a diverse patient cohort. Plasma proteins and autoantibodies were measured across seven SLE manifestations. Comparative analyses between pathologies and correlation with the SLE Disease Activity Index (SLEDAI) were used to identify proteins associated with organ-specific and composite disease activity. Established biomarkers of composite disease activity, SLE-associated antibodies, type I interferon (IFN), and complement C3, correlated with composite SLEDAI, but did not significantly associate with many individual SLE pathologies. Two clusters of proteins were associated with renal disease in lupus nephritis samples. One cluster included markers of infiltrating leukocytes and the second cluster included markers of tissue remodelling. In patients with discoid lupus, a distinct signature consisting of elevated immunoglobulin A autoantibodies and interleukin-23 was observed. Our findings indicate that proteins from blood samples can be used to identify protein signatures that are distinct from established SLE biomarkers and SLEDAI and could be used to conveniently monitor multiple inflammatory pathways present in different organ systems.


Assuntos
Lúpus Eritematoso Discoide/sangue , Lúpus Eritematoso Sistêmico/sangue , Nefrite Lúpica/sangue , Adulto , Autoanticorpos/sangue , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Inflamação/sangue , Rim/patologia , Lúpus Eritematoso Discoide/patologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade
15.
Lupus Sci Med ; 6(1): e000335, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275579

RESUMO

Gastric bypass surgery, also called Roux-en-Y gastric bypass (RYGB), can result in the malabsorption of medications, requiring the use of higher than usual doses in order to achieve a therapeutic effect. We describe the results of hydroxychloroquine (HCQ) blood levels in three patients with systemic autoimmune disease taking standard HCQ doses and their associated disease activity levels. This is a retrospective review of all patients who had undergone RYGB and were taking HCQ in a rheumatology community-based practice. Two patients with SLE and one patient with primary Sjogren's syndrome had previously undergone RYGB. All three had subtherapeutic HCQ blood levels and active disease. Increasing their HCQ doses above the recommended 400 mg a day dosing resulted in therapeutic HCQ levels in all three patients and better disease control in two of the three patients. RYGB patients may not absorb HCQ adequately, resulting in subtherapeutic HCQ blood levels and inadequate disease control. Patients who have undergone RYGB and are taking HCQ should have drug levels monitored. RYGB patients may require higher than recommended doses of HCQ in order to achieve better disease control and avoid unneeded additional immunosuppressive agents.

16.
Lupus Sci Med ; 6(1): e000317, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168400

RESUMO

The majority of patients with SLE in the USA have been prescribed hydroxychloroquine (HCQ). Given more recent guidelines, the availability of only one strength (200 mg tablets) may limit the flexibility and ability to accurately dose patients with lupus. The Lupus Foundation of America undertook a survey to assess the current landscape of HCQ tolerability and adherence.

17.
Lupus Sci Med ; 6(1): e000318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168401

RESUMO

Background: Low C3 and lupus anticoagulant (LAC) are known risk factors for thrombosis in SLE. We evaluated the association between C4d products deposited on platelets (PC4d) and thrombosis in SLE. Antiphosphatidyl serine/prothrombin (PS/PT) complex antibody was also evaluated as an alternative to LAC. Methods: This was a cross-sectional analysis of 149 consented patients with SLE (mean age: 47±1 years, 86% female) classified with (n=16) or without (n=133) thrombotic events in the past 5 years. Abnormal PC4d (≥20 units) was measured using flow cytometry. LAC and C3 were measured using dilute Russell's viper venom time (>37 s) and immunoturbidimetry, respectively. Anti-PS/PT antibody status (IgG) was measured by immunoassay. Statistical analysis consisted of logistic regression and calculation of OR estimates with 95% CI. Results: Abnormal PC4d (OR=8.4, 95% CI 2.8 to 24.8), low C3 (OR=9.5, 95% CI 3.0 to 30.3), LAC (OR=5.4, 95% CI 1.3 to 22.3) and anti-PS/PT IgG (OR=3.4, 95% CI 1.2 to 9.7) status associated with thrombosis (p<0.05). Cumulatively, the presence of PC4d, low C3 and LAC abnormalities as a composite risk score was higher in the presence of thrombosis (1.93±0.25) than in its absence (0.81±0.06) (p<0.01). Each unit of this composite risk score yielded an OR of 5.2 (95% CI 2.5 to 10.7) to have thrombosis (p<0.01). The composite risk score with anti-PS/PT antibody status instead of LAC also associated with thrombosis (p<0.01). Conclusion: A composite risk score including PC4d, low C3 and LAC was associated with recent thrombosis and acknowledges the multifactorial nature of thrombosis in SLE.

18.
Nat Immunol ; 20(7): 902-914, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209404

RESUMO

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.


Assuntos
Rim/imunologia , Nefrite Lúpica/imunologia , Biomarcadores , Biópsia , Análise por Conglomerados , Biologia Computacional/métodos , Células Epiteliais/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Interferons/metabolismo , Rim/metabolismo , Rim/patologia , Leucócitos/imunologia , Leucócitos/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Anotação de Sequência Molecular , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Célula Única , Transcriptoma
19.
Lupus Sci Med ; 6(1): e000356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31908817

RESUMO

Objective: To define the SLE phenotype associated with pulmonary hypertension using multiple autoantibodies. Methods: 207 (8%) patients with SLE with pulmonary hypertension, defined as a right ventricular systolic pressure greater than 40 mm Hg on transthoracic echocardiogram or as pulmonary artery dilatation on CT of the chest, were identified from the Hopkins Lupus Cohort (94.2% female; 56.5% African-American, 39% Caucasian; mean age 45.6 years). 53 patients were excluded from the clustering analysis due to incomplete autoantibody profiles. Agglomerative hierarchical clustering algorithm with Ward's method was used to cluster the patients with pulmonary hypertension, based on their autoantibodies. Autoantibodies used in the clustering analysis included lupus anticoagulant, anticardiolipin, anti-beta 2 glycoprotein I, antidouble-stranded DNA, anti-Sm (anti-Smith), antiribonucleoprotein, false positive-rapid plasma reagin, anti-Ro, anti-La and hypocomplementaemia (C3 ever low or C4 ever low). The Dunn index was used to internally validate the clusters. Bootstrap resampling derived the mean Jaccard coefficient for each cluster. All analyses were performed in R V.3.6.1 using the packages cluster, fpc and gplots. Results: A significantly higher prevalence of pulmonary hypertension in African-American patients with SLE, compared with Caucasian patients with SLE (11.5% vs 5.9%, p<0.0001), was found. Based on equivalent Dunn indices, the 154 patients with SLE-associated pulmonary hypertension with complete autoantibody data were divided into five clusters, three of which had mean Jaccard coefficients greater than 0.6. Hypocomplementaemia, renal disorder and age at diagnosis significantly differed across clusters. One cluster was defined by antiphospholipid antibodies. One cluster was defined by anti-Ro and anti-La. One cluster had low frequencies of all antibodies. Conclusion: SLE-associated pulmonary hypertension disproportionately affects African-American patients. Pulmonary hypertension in SLE is defined by five autoantibody clusters. Antiphospholipid antibodies, anti-Ro and anti-La positivity, serological activity, and age at pulmonary hypertension diagnosis significantly differed across clusters, possibly indicating different pathophysiological mechanisms.

20.
Lupus Sci Med ; 5(1): e000287, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538818

RESUMO

Objectives: The aim of this study is to identify prognostic factors of persistent disease activity and long quiescence in systemic lupus erythematosus (SLE). Methods: Patients enrolled in the Hopkins Lupus Cohort from 1987 to 2012, who attended at least three visits per year during 3 consecutive years following baseline and had available information on disease activity were included. Patterns of SLE disease activity over the 3-year period were defined as: persistent long quiescent (pLQ), persistent relapsing-remitting (pRR), persistent chronic active (pCA) and mixed based on Modified SLE Disease Activity Index (M-SLEDAI). Possible predictors of pCA (vs pLQ, pRR and mixed) and pLQ (vs pCA, pRR and mixed) were identified by univariate and multivariate logistic regression analyses. Results: 916 patients were included. In the multivariate analysis, use of hydroxychloroquine (OR: 0.45, 95% CI 0.22 to 0.92, p=0.03), African American ethnicity (OR: 2.36, 95% CI 1.15 to 4.85, p=0.02) and baseline SLEDAI (OR: 1.10, 95% CI 1.03 to 1.17, p=0.005) remained significant predictors of pCA. Higher education (>12 years; OR. 2.07, 95% CI 1.07 to 4.03, p=0.03) and lower baseline SLEDAI (OR: 0.67, 95% CI 0.56 to 0.82, p<0.001) were significant predictors of pLQ, while African American (OR: 0.38, 95% CI 0.17 to 0.83, p=0.02) and female patients (OR: 0.26, 95% CI 0.12 to 0.57, p<0.001) were less likely to achieve pLQ. Conclusion: African American ethnicity and high disease activity at baseline predict chronic activity in SLE, regardless of treatment, years of education and income. Higher education, low disease activity at baseline and male sex predict long quiescence. The use of hydroxychloroquine is independently associated with a lower risk of chronically active disease.

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