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Platelet-bound complement activation products (PC4d) are associated with thrombosis in Systemic Lupus Erythematosus (SLE). This study investigated the effect of PC4d on platelet function, as a mechanistic link to arterial thrombosis. In a cohort of 150 SLE patients, 13 events had occurred within five years of enrollment. Patients with arterial events had higher PC4d levels (13.6 [4.4-24.0] vs. 4.0 [2.5-8.3] net MFI), with PC4d 10 being the optimal cutoff for event detection. The association of arterial events with PC4d remained significant after adjusting for antiphospholipid status, smoking, and prednisone use (p = 0.045). PC4d levels correlated with lower platelet counts (r = -0.26, p = 0.002), larger platelet volumes (r = 0.22, p = 0.009) and increased platelet aggregation: the adenosine diphosphate (ADP) concentration to achieve 50% maximal aggregation (EC50) was lower in patients with PC4d 10 compared with PC4d < 10 (1.6 vs. 3.7, p = 0.038, respectively). These results suggest that PC4d may be a mechanistic marker for vascular disease in SLE.
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Plaquetas/metabolismo , Ativação do Complemento/imunologia , Complemento C4/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/metabolismo , Ativação Plaquetária/genética , Doenças Vasculares/etiologia , Difosfato de Adenosina/metabolismo , Autoanticorpos/imunologia , Autoimunidade , Biomarcadores , Plaquetas/imunologia , Complemento C4/metabolismo , Suscetibilidade a Doenças , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Ativação Plaquetária/imunologia , Agregação Plaquetária , Contagem de Plaquetas , Trombose/etiologia , Trombose/metabolismo , Doenças Vasculares/metabolismoRESUMO
PURPOSE OF REVIEW: Three COVID-19 vaccines obtained emergency authorization from the Food and Drug Administration (FDA) and are widely used in the USA. Unfortunately, there is a paucity of evidence on the safety and efficacy of these vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD), as these patients were excluded from all phases of vaccine development. Here we reviewed current data on COVID-19 vaccination in patients with AIIRD, with emphasis on systemic lupus erythematosus (SLE), and provided a comprehensive update on the benefits and risks of vaccination. RECENT FINDINGS: Patients with SLE have worse immune responses following SARS-CoV-2 vaccination than healthy controls. The efficacy of the COVID-19 vaccines seems to be further reduced by immunosuppressive medications, such as glucocorticoids (GC), methotrexate (MTX), mycophenolate/mycophenolic acid (MMF), and rituximab (RTX). However, these data do not substantiate that AIIRD patients are at greater risk of disease flares or have a higher incidence of side effects following vaccination. There is no significant safety concern for the use of COVID-19 vaccines in patients with AIIRD. The benefits of vaccination far outweigh the risks in patients with AIIRD, including SLE. More data are needed to determine the necessity of a booster vaccine dose and appropriate adjustment of immunosuppressants around the administration of vaccine.
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Doenças Autoimunes , COVID-19 , Lúpus Eritematoso Sistêmico , Doenças Reumáticas , Vacinas , Vacinas contra COVID-19 , Humanos , SARS-CoV-2 , Estados UnidosRESUMO
Targeting immune checkpoint receptors on T cells is a common cancer treatment strategy. Frequently, this is accomplished through antibodies targeting the ligand of inhibitory co-receptors. Blocking the immune checkpoint PD-1 binding to its ligands PD-L1 and PD-L2 prevents downstream signaling and enhances anti-tumor T cell responses. This approach improves cancer patients' outcomes. However, only one-third of the patients respond to these treatments. To better understand the mechanism of anti-PD-1 antibodies, we explored the location of PD-1 within the immune synapse. Surprisingly, we discovered that anti-PD-1 antibodies, besides blocking the interaction between PD-1 and its ligands, also removed PD-1 from the synapse. We demonstrated a correlation between removing PD-1 from the synapse by anti-PD-1 antibodies and the extent of T cell activation. Interestingly, a short version of the anti-PD-1 antibody, F(ab')2, failed to remove PD-1 from the synapse and activate T cells. Using the syngeneic tumor model, we showed a superior anti-tumor effect of the anti-PD-1 antibody over the shorter version of the same antibody. Our data indicate that anti-PD-1 antibodies activate T cells by removing PD-1 from the synapse, and changing the location of PD-1 or other immune receptors within the immune synapse could serve as an alternative, efficient approach to treat cancer.
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BACKGROUND: PD-1 is an immune checkpoint on T cells, and interventions to block this receptor result in T cell activation and enhanced immune response to tumors and pathogens. Reciprocally, despite a decade of research, approaches to treat autoimmunity with PD-1 agonists have only had limited successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor. METHODS: We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis. In addition, we performed a genome-wide CRISPR/Cas9 screen to identify genes associated with PD-1 signaling. We further analyzed genes involved in PD-1 signaling using publicly available bulk and single-cell RNA sequencing datasets. RESULTS: Our screen confirmed known regulators in proximal PD-1 signaling and, importantly, identified an additional 1112 unique genes related to PD-1 ability to inhibit T cell functions. These genes were strongly associated with the response of cancer patients to PD-1 blockades and with high tumor immune dysfunction and exclusion scores, confirming their role downstream of PD-1. Functional annotation revealed that the most significant genes uncovered were those associated with known immune regulation processes. Remarkably, these genes were considerably downregulated in T cells isolated from patients with inflammatory arthritis, supporting their overall inhibitory functions. A study of rheumatoid arthritis single-cell RNA sequencing data demonstrated that five genes, KLRG1, CRTAM, SLAMF7, PTPN2, and KLRD1, were downregulated in activated and effector T cells isolated from synovial fluids. Backgating these genes to canonical cytotoxic T cell signatures revealed PD-1+ HLA-DRHIGH KLRG1LOW T cells as a novel inflammatory subset of T cells. CONCLUSIONS: We concluded that PD-1+ HLA-DRHIGH KLRG1LOW T cells are a potential target for future PD-1 agonists to treat inflammatory diseases. Our study uncovers new genes associated with PD-1 downstream functions and, therefore, provides a comprehensive resource for additional studies that are much needed to characterize the role of PD-1 in the synovial subset of T cells.
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Artrite Reumatoide , Receptor de Morte Celular Programada 1 , Humanos , Receptor de Morte Celular Programada 1/genética , Artrite Reumatoide/genética , Transdução de Sinais , Linfócitos T Citotóxicos , Antígenos HLA-DRRESUMO
Introduction: T follicular (TFH) and peripheral helper (TPH) cells have been increasingly recognized as a pathogenic subset of CD4 T cells in systemic lupus erythematosus (SLE). The SLAM Associated Protein (SAP) regulates TFH and TPH function by binding to the co-stimulatory signaling lymphocyte activation molecule family (SLAMF) receptors that mediate T cell - B cell interactions. SAP and SLAMF are critical for TPH-dependent B cell maturation into autoantibody-producing plasma cells that characterize SLE pathogenesis. We hypothesized that SAP-expressing TPH cells are involved in the pathogenesis of lupus nephritis (LN). Methods: Peripheral blood mononuclear cells (PBMC) were isolated using density gradient separation from whole blood. Cells were stained for cell surface markers, followed by permeabilization and staining of intracellular SAP for spectral flow cytometry analysis. We also analyzed SAP expression from renal infiltrating LN T cells using the available single-cell RNA sequencing (scRNA seq) Accelerated Medicines Partnership (AMP) SLE dataset. Results: PBMC from 30 patients with SLE (34 ± 10 years old, 83% female), including 10 patients with LN, were analyzed. We found an increase in total SAP-positive CD4 and CD8 T cells in SLE compared with controls (55.5 ± 2.6 vs. 41.3 ± 3.4, p=0.007, and 52.5 ± 3.0 vs. 39.2 ± 2.8, p=0.007 respectively). In CD4 T cells, the highest SAP expression was in the TPH subset. The frequency of SAP+TPH in circulation correlated with disease activity; SLE patients with renal disease had higher levels of circulating SAP+TPH that remained significant after adjusting for age, sex, race, low complements, and elevated anti-dsDNA (p=0.014). scRNA-seq data of renal infiltrating T cells in LN identified SAP expression to localize to the TFH-like CD4 cluster and GZMK+ CD8 cluster. Increased SAP expression in LN was associated with the differential expression of SLAMF3 and SLAMF7 and granzyme K and EOMES. The existence of two predominant SAP-expressing subsets, the TFH-like CD4 T cells, and GZMK+ effector CD8 T cells, was verified using scRNA-seq data from a human transcriptomic atlas of fifteen major organs. Conclusion: The expansion of SAP-expressing T helper cells was associated with LN in our cohort and verified using scRNA-seq data of renal infiltrating T cells. Improved SLAM and SAP signaling understanding can identify new therapeutic targets in LN.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Feminino , Adulto Jovem , Adulto , Masculino , Nefrite Lúpica/metabolismo , Leucócitos Mononucleares/metabolismo , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Rheumatologic diseases are characterised by loss of immune tolerance, resulting in systemic inflammation. Inflammation and scarring of the endocardium, which lines the inner surface of the heart chambers and valves, can result in valvular thickening and dysfunction. Estimates of prevalence vary depending on the sensitivity of the screening methodology used and range from 30%-50% in systemic lupus and rheumatoid arthritis to 10%-30% in ankylosing spondylitis. Progression of valve disease is a slow process but can result in haemodynamically significant complications. Thromboembolic complications such as cerebrovascular occlusions pose a serious risk of morbidity. The presence of antiphospholipid antibodies increases the risk of valvular disease and thrombotic complications. Anticoagulation is recommended in the presence of antiphospholipid antibodies, but the guidance on the role of immunosuppressive therapy to treat valvular disease is lacking. Surgical valve therapy may be considered in severe disease, but there is increased risk in patients with an autoimmune disease which includes a higher risk of infection, thromboembolic and bleeding complications, as well as cardiovascular events in the setting of premature atherosclerotic heart disease. Therefore, management should be provided in a multidisciplinary team that includes a rheumatologist, a cardiologist and a cardiothoracic surgeon; medical therapy should be optimised before considering a high-risk valve surgery.
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Síndrome Antifosfolipídica , Doenças Autoimunes , Doenças das Valvas Cardíacas , Tromboembolia , Trombose , Humanos , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/terapia , Doenças das Valvas Cardíacas/diagnóstico , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Trombose/complicações , Anticorpos Antifosfolipídeos , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , InflamaçãoRESUMO
Signaling lymphocyte activation molecule family member 6 (SLAMF6) is a T cell co-receptor. Previously, we showed that SLAMF6 clustering was required for T cell activation. To better understand the relationship between SLAMF6 location and function and to evaluate the role of SLAMF6 as a therapeutic target, we investigated how its compartmentalization on the cell surface affects T cell functions. We used biochemical and co-culture assays to show that T cell activity is enhanced when SLAMF6 colocalizes with the CD3 complex. Mechanistically, co-immunoprecipitation analysis revealed the SLAMF6-interacting proteins to be those essential for signaling downstream of T cell receptor, suggesting the two receptors share downstream signaling pathways. Bispecific anti-CD3/SLAMF6 antibodies, designed to promote SLAMF6 clustering with CD3, enhanced T cell activation. Meanwhile, anti-CD45/SLAMF6 antibodies inhibited SLAMF6 clustering with T cell receptor, likely because of the steric hindrance, but nevertheless enhanced T cell activation. We conclude that SLAMF6 bispecific antibodies have a role in modulating T cell responses, and future work will evaluate the therapeutic potential in tumor models.
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Receptores de Antígenos de Linfócitos T , Linfócitos T , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Platelet-bound complement activation product C4d (PC4d) levels correlate with history of thrombosis in patients with systemic lupus erythematosus (SLE). The present study evaluated whether PC4d levels could assess risk of future thrombosis events. METHODS: PC4d level was measured by flow cytometry. Thromboses were confirmed by electronic medical record data review. RESULTS: The study included 418 patients. Nineteen events (13 arterial and 6 venous) occurred in 15 subjects in the 3 years post-PC4d level measurement. PC4d levels above the optimum cutoff of 13 mean fluorescence intensity (MFI) predicted future arterial thrombosis with a hazard ratio of 4.34 (95% confidence interval [95% CI] 1.03-18.3) (P = 0.046) and a diagnostic odds ratio (OR) of 4.30 (95% CI 1.19-15.54). Negative predictive value of PC4d level of ≤13 MFI for arterial thrombosis was 99% (95% CI 97-100%). Although a PC4d level of >13 MFI did not reach statistical significance for prediction of total thrombosis (arterial and venous) (diagnostics OR 2.50 [95% CI 0.88-7.06]; P = 0.08), it was associated with all thrombosis (n = 70 historic and future arterial and venous events in the 5 years pre- to 3 years post-PC4d level measurement) with an OR of 2.45 (95% CI 1.37-4.32; P = 0.0016). In addition, the negative predictive value of PC4d level of ≤13 MFI for all future thrombosis events was 97% (95% CI 95-99%). CONCLUSIONS: A PC4d level of >13 MFI predicted future arterial thrombosis and was associated with all thrombosis. Patients with SLE presenting with a PC4d level of ≤13 MFI had high probability of not experiencing arterial or any thrombosis in the 3 years afterwards. Taken together, these findings indicate that PC4d levels may help predict the risk of future thrombosis events in SLE.
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Lúpus Eritematoso Sistêmico , Trombose , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Trombose/diagnóstico , Trombose/epidemiologia , Trombose/etiologia , Plaquetas , Fatores de RiscoRESUMO
PD-1 is an inhibitory receptor in T cells, and antibodies that block its interaction with ligands augment anti-tumor immune responses. The clinical potential of these agents is limited by the fact that half of all patients develop immune-related adverse events (irAEs). To generate insights into the cellular changes that occur during anti-PD-1 treatment, we performed single-cell RNA sequencing of circulating T cells collected from patients with cancer. Using the K-nearest-neighbor-based network graph-drawing layout, we show the involvement of distinctive genes and subpopulations of T cells. We identify that at baseline, patients with arthritis have fewer CD8 TCM cells, patients with pneumonitis have more CD4 TH2 cells, and patients with thyroiditis have more CD4 TH17 cells when compared with patients who do not develop irAEs. These data support the hypothesis that different populations of T cells are associated with different irAEs and that characterization of these cells' pre-treatment has the potential to serve as a toxicity-specific predictive biomarker.
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Neoplasias , Linfócitos T , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Imunidade , Imunoterapia/efeitos adversos , Análise de Sequência de RNARESUMO
Background: The pandemic disrupted the care of patients with rheumatic diseases; difficulties in access to care and its psychological impact affected quality of life. Telemedicine as an alternative to traditional face-to-face office visits has the potential to mitigate this impact. Objective: To evaluate patient and provider experience with telemedicine and its effect on care. Methods: We surveyed patients with rheumatic diseases and their rheumatology providers. The surveys were conducted in 2020 and repeated in 2021. We assessed data on quality of care and health-related quality of life. Results: Hundred patients and 17 providers responded to the survey. Patients reported higher satisfaction with telemedicine in 2021 compared to 2020 (94 vs. 84%), felt more comfortable with (96 vs. 86%), expressed a stronger preference for (22 vs. 16%), and higher intention to use telemedicine in the future (83 vs. 77%); patients thought physicians were able to address their concerns. While providers' satisfaction with telemedicine increased (18-76%), 14/17 providers believed that telemedicine visits were worse than in-person visits. There were no differences in annualized office visits and admissions. Mean EQ-5D score was 0.74, lower than general population (0.87) but equivalent to a subset of patients with SLE (0.74). Conclusion: Our data showed a high level of satisfaction with telemedicine. The lower rheumatology provider satisfaction raises concern if telemedicine constitutes an acceptable alternative to in-person care. The stable number of office visits, admissions, and the similar quality of life to pre-pandemic level suggest effective management of rheumatic diseases using telemedicine/in-person hybrid care.
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T cell activation is the result of the integration of signals across the T cell receptor and adjacent co-receptors. The signaling lymphocyte activation molecules (SLAM) family are transmembrane co-receptors that modulate antigen driven T cell responses. Signal transduction downstream of the SLAM receptor is mediated by the adaptor protein SLAM Associated Protein (SAP), a small intracellular protein with a single SH2 binding domain that can recruit tyrosine kinases as well as shield phosphorylated sites from dephosphorylation. Balanced SLAM-SAP signaling within T cells is required for healthy immunity, with deficiency or overexpression prompting autoimmune diseases. Better understanding of the molecular pathways involved in the intracellular signaling downstream of SLAM could provide treatment targets for these autoimmune diseases.
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Autoimunidade , Transdução de Sinais , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Comunicação Celular/imunologia , Suscetibilidade a Doenças , Genes Ligados ao Cromossomo X , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Ligação Proteica , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismoRESUMO
Since the first outbreak of Coronavirus Disease-2019 (COVID-19) in January 2020, the medical community has been pursuing effective countermeasures. Early in the pandemic, several small clinical and in vitro studies from France and China reported on the efficacy of chloroquine (CQ) and hydroxychloroquine (HCQ) against SARS-CoV-2 infections, which generated global attention towards these decades-old antimalarials (AM) and heralded numerous studies investigating their role in treating COVID-19. Despite several observational studies early in the pandemic affirming their beneficial role in treating COVID-19, 12 clinical studies reported no mortality benefits for CQ/HCQ in COVID-19 patients. The excitement over CQ/HCQ was ultimately quenched after three large randomized clinical trials, the COALITION-I trial in Brazil, the RECOVERY trial in the United Kingdom (UK), and the SOLIDARITY trial from World Health Organization (WHO) consistently reported no beneficial effects for CQ/HCQ in hospitalized COVID-19 patients. While initial studies suggested that CQ/HCQ might have a role in treating the early phases of infection, the results from three rigorously designed studies investigating their role in non-hospitalized COVID-19 patients were equivocal and inconsistent. Here we review the major social events related to the therapeutic use of CQ/HCQ in COVID-19, and the data from selected clinical studies evaluating their efficacy in hospitalized and non-hospitalized COVID-19 patients along with the major safety concerns.
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BackgroundHydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, reports of its use and subsequent fatal arrhythmias in patients with Coronavirus disease 19 (COVID-19) have raised concern regarding its cardiovascular (CV) safety. Therefore, we examined the relationship between HCQ use and corrected QT (QTc) length in SLE and RA patients without clinical CV disease (CVD).MethodsOne SLE (n=352) and two RA cohorts (n=178) with electrocardiograms (ECGs) collected as part of study data were analyzed. RA cohort participants were recruited from tertiary referral centers with additional referrals from community rheumatologists, while SLE subjects originated from the Columbia University Lupus Cohort. All patients met American College of Rheumatology (ACR) classification criteria for SLE or RA, and lacked known CVD. The exposure of interest was HCQ use and main outcome measure was QTc length [continuous or categorical (≥440 ms and ≥500 ms)]. ResultsOf the combined SLE and RA cohorts (n=530), 70% were HCQ users and 44% had a QTc≥ 440 ms. The adjusted mean QTc length was comparable between HCQ users vs non-users (438 ms vs 437 ms). In multivariable logistic models, HCQ use was not a significant predictor of a QTc≥440 ms for the entire cohort (OR 0.77; 95% CI 0.48-1.23; p=0.27). Importantly, a QTc≥500 ms was inversely associated with HCQ use and not associated with arrhythmias or deaths. A significant interaction was found between HCQ use and use of anti-psychotics. Ultimately, the use of HCQ combined with any QTc prolonging medication as a group was associated with a QTc length (434 ms; 95%CI 430, 439) which was comparable to that of use of HCQ alone (433 ms; 95% CI 429, 437). ConclusionIn a combined cohort of SLE and RA patients without clinical CVD, adjusted QTc length was comparable between HCQ and non-HCQ users, supporting its CV safety in patients with rheumatic diseases.
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BACKGROUND: Hydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, reports of its use and subsequent fatal arrhythmias in patients with coronavirus disease 19 (COVID-19) have raised concern regarding its cardiovascular (CV) safety. Therefore, we examined the relationship between HCQ use and corrected QT (QTc) length in SLE and RA patients without clinical CV disease (CVD). METHODS: SLE patients from the Columbia University Lupus Cohort registry (n = 352) and two RA cohorts (n = 178; ESCAPE-RA and RHYTHM-RA) with electrocardiograms (ECGs) collected as part of study data were analyzed. RA cohort participants were recruited from tertiary referral centers with additional referrals from community rheumatologists, while SLE subjects originated from the Columbia University Lupus Cohort. All patients met American College of Rheumatology (ACR) classification criteria for SLE or RA and lacked known CVD. The exposure of interest was HCQ use and main outcome measure was QTc length [continuous or categorical (≥ 440 ms and ≥ 500 ms)]. RESULTS: Of the combined SLE and RA cohorts (n = 530), 70% were HCQ users and 44% had a QTc ≥ 440 ms. The adjusted mean QTc length was comparable between HCQ users vs non-users (438 ms vs 437 ms). In multivariable logistic models, HCQ use was not a significant predictor of a QTc ≥ 440 ms for the entire cohort (OR 0.77; 95% CI 0.48-1.23; p = 0.27). Importantly, a QTc ≥ 500 ms was inversely associated with HCQ use and not associated with arrhythmias or deaths. A significant interaction was found between HCQ use and use of anti-psychotics. Ultimately, the use of HCQ combined with any QTc prolonging medication as a group was associated with a QTc length (434 ms; 95% CI 430, 439) which was comparable to that of use of HCQ alone (433 ms; 95% CI 429-437). CONCLUSION: In a combined cohort of SLE and RA patients without clinical CVD, adjusted QTc length was comparable between HCQ and non-HCQ users, supporting its CV safety in patients with rheumatic diseases.
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We have developed a flexible optical imaging system (FOIS) to assess systemic lupus erythematosus (SLE) arthritis in the finger joints. While any part of the body can be affected, arthritis in the finger joints is one of the most common SLE manifestations. There is an unmet need for accurate, low-cost assessment of lupus arthritis that can be easily performed at every clinic visit. Current imaging methods are imprecise, expensive, and time consuming to allow for frequent monitoring. Our FOIS can be wrapped around joints, and multiple light sources and detectors gather reflected and transmitted light intensities. Using data from two SLE patients and two healthy volunteers, we demonstrate the potential of this FOIS for assessment of arthritis in SLE patients.
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OBJECTIVES: Systemic lupus erythematosus (SLE) affects the joints in up to 95% of patients. The diagnosis and evaluation of SLE arthritis remain challenging in both practice and clinical trials. Frequency domain optical imaging (FDOI) has been previously used to assess joint involvement in inflammatory arthritis. The objective of this study was to evaluate FDOI in SLE arthritis. METHODS: Ninety-six proximal interphalangeal (PIP) joints from 16 patients with SLE arthritis and 60 PIP joints from 10 age-matched, gender-matched and race/ethnicity-matched controls were examined. A laser beam with a wavelength of 670 nm, 1 mm in diameter and intensity modulated at 300 MHz and 600 MHz was directed onto the dorsal surface of each joint, scanning across a sagittal plane. The transmitted light intensities and phase shifts were measured with an intensified charge-coupled device camera. The data were analysed using Discriminant Analysis and Support Vector Machine algorithms. RESULTS: The amplitude and phase of the transmitted light were significantly different between SLE and control PIPs (p<0.05). Receiver operating characteristic (ROC) analysis of cross-validated models showed an Area Under the ROC Curve (AUC)of 0.89 with corresponding sensitivity of 95%, specificity of 79%, and accuracy of 80%. CONCLUSION: This study is the first evaluation of optical methods in the assessment of SLE arthritis; there was a statistically significant difference in the FDOI signals between patients with SLE and healthy volunteers. The results show that FDOI may have the potential to provide an objective, user-independent, evaluation of SLE PIP joints arthritis.
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Artrite , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Imagem Óptica , Curva ROCRESUMO
OBJECTIVE: Hydroxychloroquine (HCQ) retinal toxicity is an ongoing concern for rheumatologists. The revised 2016 American Academy of Ophthalmology (AAO) guidelines created controversy regarding the correct dosing and evaluation of HCQ toxicity. The current study was initiated to further understand rheumatologists' practices regarding HCQ. METHODS: A questionnaire-based survey was distributed electronically to rheumatologists. We collected information on HCQ dosing, clinical decision-making processes, familiarity with the AAO 2016 guidelines, and perceived disparities between the AAO 2016 guidelines and rheumatological clinical practice. RESULTS: 78 rheumatologists completed the survey (49% from USA, 90% academic practices, 82% self-identified as lupus experts). Only lupus expert (n=64) data were included in subsequent analysis. The mean cohort size was 747 (50-6571), a total cohort 45 612 patients. HCQ was prescribed to >75% of patients with SLE by 81.3% of SLE experts, with routine counselling about ophthalmic risks. The typical dose of HCQ used was 200-400 mg/day. 17% of rheumatologists use doses up to 600 mg/day, while 6.2% use up to 6.5 mg/kg/day. HCQ adherence is routinely assessed. 479 cases of HCQ retinal toxicity (1.05%) and 9 cases of HCQ-associated blindness (1.8 per 10 000 patients) were reported. 89.1% of respondents reported familiarity with the AAO guidelines. Those aware of the guidelines cited limited dosing options (54.7%), lack of supporting evidence (57.8%) and low patient adherence (43.8%) as obstacles to greater implementation of the guidelines. CONCLUSION: These data suggest that HCQ toxicity and blindness are rare in patients with SLE. Rheumatologists treating patients with SLE are aware of the guidelines and appreciate the importance of partnering with ophthalmologists in preventing retinal toxicity.
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Hidroxicloroquina/uso terapêutico , Adulto , Antirreumáticos , Estudos de Coortes , Feminino , Humanos , Oftalmologistas , Reumatologistas , Estados UnidosRESUMO
OBJECTIVE: To define the risk of progressive multifocal leukoencephalopathy (PML) in SLE. METHODS: This is a retrospective observational study to evaluate PML cases in patients with SLE admitted to two large academic hospitals. Using electronic medical record (EMR) data, International Classification of Diseases (ICD) codes identified PML cases among patients with SLE, rheumatoid arthritis (RA) (controls), had renal transplant and with HIV. Medication exposure was reviewed. RESULTS: A total of 5409 Columbia University Medical Center (CUMC) patients and 2046 Northwell Health patients were identified using one ICD code for SLE. Of 7455 patients, three had an ICD code for PML. On EMR review, however, PML was substantiated in only one fatal SLE case with significant immunosuppressant use and severe lymphopenia (<0.5 cells x 109/L); one patient was evaluated for PML but cerebrospinal fluid (CSF) was negative for JC virus and improved with treatment of central nervous system (CNS) lupus. EMR data were very limited for the third patient and diagnosis could not be confirmed. None of the 13 342 patients with RA ICD codes had PML. Of the 5409 patients with an SLE ICD code at CUMC, 212 also had a renal transplant ICD code, and 83 had concomitant HIV/AIDS. Based on inpatient pharmacy records of 5409 hospitalised patients at CUMC, 59.2% were treated with steroids, and 16.09% with immunosuppressants (7.76% mycophenolate, 3.42% cyclophosphamide, 2.88% azathioprine and 2.03% rituximab). No patients with paediatric SLE (pSLE) (n=538) had PML. The combined prevalence of PML in hospitalised patients with SLE at the two hospitals was 13-27/100 000 patients. CONCLUSION: Among 7455 adult patients with SLE ICD codes, there were two PML cases, with only one confirmed case associated with severe lymphopenia and immunosuppressants, corresponding to a prevalence of 13-27 per 100 000 patients. No PML cases in pSLE were found. A high index of suspicion in patients with SLE and CNS manifestations is required for the prompt diagnosis of PML.
Assuntos
Artrite Reumatoide/complicações , Imunossupressores/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/etiologia , Lúpus Eritematoso Sistêmico/complicações , Adulto , Estudos de Casos e Controles , Viroses do Sistema Nervoso Central/epidemiologia , Viroses do Sistema Nervoso Central/virologia , Criança , Registros Eletrônicos de Saúde , Feminino , HIV/isolamento & purificação , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Hospitalização , Humanos , Imunossupressores/uso terapêutico , Vírus JC/isolamento & purificação , Transplante de Rim/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/epidemiologia , Leucoencefalopatia Multifocal Progressiva/virologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Linfopenia/complicações , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Medição de RiscoRESUMO
OBJECTIVES: Cardiovascular disease (CVD) is a leading cause of death in SLE. Coronary artery calcium (CAC) scores predict CVD events, independent of traditional risk factors. Patients with SLE aged >45 years have an increased prevalence of CAC in a predominantly white population. Little is known about CAC in younger patients with SLE. We evaluated CAC in younger patients with SLE of predominantly African-American and Hispanic ancestry, compared with healthy controls. METHODS: We identified 76 patients with SLE meeting 1997 American College of Rheumatology classification criteria, without known coronary artery disease and who had a non-contrast chest CT performed as part of their clinical care, with images retrievable for calculation of CAC scores. Demographics, disease characteristics and comorbidities were ascertained and adjusted for. RESULTS: 42.1% of patients with SLE (mean age 40±13 years, 90% female, 33% Hispanic and 40% African-American) had CAC>0, 32% for age ≤45 years and 61.6% for age >45. Patients with SLE with CAC>0 were older and had more comorbid hypertension. Women with SLE aged ≤45 years, had a 12.6-fold higher adjusted odds of CAC>0 compared with age-matched and sex-matched controls (95% CI 5.2 to 30.7, p<0.001). Furthermore, 29% of patients with SLE aged 18-32 years (median disease duration of 5 years) had CAC>0. CONCLUSION: Patients with SLE aged ≤45 years have an increased prevalence of detectable CAC compared with the general population. Our data suggest that subclinical atherosclerosis in SLE develops early and warrants timely screening and cardioprotective interventions.
RESUMO
OBJECTIVES: Lupus nephritis (LN) requires renal replacement therapy in 10%-30% of patients. About 30% of these patients receive a kidney transplant. Belatacept is a second-generation, selective, T-cell co-stimulator blocker (inhibits cytotoxic, T-lymphocyte antigen 4, CTLA-4) used as an alternative to calcineurin inhibitors (CNI) for maintenance regimens after kidney transplantation. The pathogenic relevance of CTLA-4 inhibition and the favourable cardiovascular profile of belatacept make it an attractive therapeutic option in systemic lupus erythematosus (SLE). Intravenous administration of belatacept ensures therapeutic adherence. METHODS: This retrospective, single-centre study evaluates the outcomes of LN kidney transplant recipients treated with belatacept for reasons not related to SLE at the Columbia University Lupus and Renal Transplant Cohort. RESULTS: Belatacept was started in six patients on CNI regimens at 15.5±17.1 months following transplantation for LN. In five patients, creatinine levels stabilised 6 months after belatacept, one returned to haemodialysis due to CNI toxicity and pyelonephritis and one relisted for a kidney transplant following acute cellular rejection and cortical necrosis. Five patients are followed for extrarenal lupus; no extrarenal manifestations were documented in the other two patients. Data on SLE disease activity pre-belatacept and post-belatacept were available and scored in three patients using the SLE Disease Activity Index Glucocorticosteroid Index (SLEDAI-2KG), which accounts for clinical and laboratory manifestations, as well as steroid dose. Mean SLEDAI-2KG decreased from 13 to 7.6. CONCLUSION: Belatacept in LN kidney transplant recipients may decrease extrarenal manifestations, attenuate CNI toxicity and stabilise allograft function, providing a better alternative to CNI regimens. Furthermore, these data suggest that belatacept, although initiated for reasons not related to SLE, might have a beneficial effect in SLE.