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1.
Lupus ; 33(9): 938-947, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38860319

RESUMEN

OBJECTIVE: To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). METHODS: We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/µL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/µL in ≤6 months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. RESULTS: There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/µL in T1 and 160 cells/µL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. CONCLUSION: Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Linfocitos B , Nefritis Lúpica , Rituximab , Humanos , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Rituximab/uso terapéutico , Rituximab/efectos adversos , Femenino , Estudios Retrospectivos , Adulto , Masculino , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Recuento de Linfocitos , Persona de Mediana Edad , Resultado del Tratamiento , Inmunosupresores/uso terapéutico , Adulto Joven , Brote de los Síntomas , Factores Inmunológicos/uso terapéutico
2.
Rheumatology (Oxford) ; 62(7): 2534-2538, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-36355567

RESUMEN

OBJECTIVES: To investigate the expression of type I IFN (IFN-I) and neutrophil transcripts in kidney tissue from patients with different classes of LN and their association with distinct clinical and histopathological features. METHODS: Quantitation of IFN-I, defensin-α3 and formyl peptide receptor-like 1 (FPRL-1) transcripts was performed in kidney biopsy tissue from 24 patients with various classes of LN (6 class III, 14 class IV, 4 class V) and 3 control samples. Patient demographics, glomerular filtration rate (eGFR) and histopathological characteristics, including activity and chronicity indices, were analysed. RESULTS: IFNα2 and IFNß transcripts were overexpressed in renal tissues from patients with proliferative forms of LN (III/IV) compared with patients with membranous nephritis and control kidneys. Patients with LN and impaired renal function, attested by eGFR, displayed higher relative expression of IFNα2 transcripts in renal tissues compared with those with normal renal function (23.0 ± 16.2 vs 12.0 ± 14.8, P = 0.04). Defensin-α3, but not FPRL-1, transcripts were overexpressed in LN tissues, particularly those with segmental necrotizing lesions, and were correlated with higher renal pathological activity indices (r = 0.61, P = 0.02), urinary protein levels (r = 0.44, P = 0.048) and IFNα2 expression (r = 0.50, P = 0.01). CONCLUSION: IFN-I transcripts are expressed locally in kidneys from patients with proliferative LN and are associated with impaired renal function. Elevated defensin-α3 transcripts, a neutrophil product associated with neutrophil extracellular traps, may identify a driver of local IFN-I expression. These findings provide insights into the mechanisms of proliferative LN and may inform therapeutic decisions regarding selection of IFN-I pathway inhibitors.


Asunto(s)
Nefritis Lúpica , Humanos , Nefritis Lúpica/tratamiento farmacológico , Neutrófilos/metabolismo , Riñón/patología , Biopsia , Defensinas/uso terapéutico
3.
Clin Immunol ; 223: 108649, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33326823

RESUMEN

OBJECTIVE: To explore whether APOBEC family members are involved in the response to inappropriate expression of L1 retroelements in primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE), as well as in SS related lymphomagenesis. METHODS: Minor salivary glands (MSG) and kidney biopsy (KB) specimens were obtained from 41 SS patients (10 with lymphoma) and 23 patients with SLE, respectively. PBMC and sera were also collected from 73 SLE patients. Full-length L1 transcripts, members of the APOBEC and IFN family were quantitated by real time PCR. Type I IFN activity was assessed in lupus plasma by a cell assay. RESULTS: APOBEC3A was increased in SS MSG, SLE KB and PBMC and correlated with L1. AID and APOBEC3G were particularly overexpressed in MSG tissues derived from SS lymphoma patients. CONCLUSION: These data reveal a previously unappreciated role of APOBEC family proteins in the pathogenesis of systemic autoimmunity and SS related lymphomagenesis.


Asunto(s)
Citidina Desaminasa/metabolismo , Retrovirus Endógenos/genética , Riñón/fisiología , Leucocitos Mononucleares/inmunología , Lupus Eritematoso Sistémico/inmunología , Linfoma/inmunología , Proteínas/metabolismo , Glándulas Salivales/fisiología , Síndrome de Sjögren/inmunología , Autoinmunidad , Transformación Celular Neoplásica , Células Cultivadas , Citidina Desaminasa/genética , Regulación de la Expresión Génica , Humanos , Interferones/metabolismo , Proteínas/genética
4.
J Autoimmun ; 88: 75-82, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29074164

RESUMEN

OBJECTIVE: To investigate whether altered DNA methylation contributes to the inappropriate expression of LINE-1 (L1) retroelements in primary Sjogren's syndrome (SS) and systemic lupus erythematosus (SLE). METHODS: Minor salivary glands (MSG) were obtained from 42 patients with primary SS [23 without adverse predictors for lymphoma development (SS-low risk), 7 SS-high risk and 12 complicated by B-cell lymphoma (SS-lymphoma)] and 17 sicca controls (SC). Additionally, kidney biopsy specimens and PBMCs were obtained from 23 and 73 lupus patients, respectively. Relative mRNA expression was quantified for full-length L1 transcripts, along with mediators of methylation. In an independent set of 44 MSG samples (11 SS-low risk, 10 SS-high risk, 15 SS-lymphoma and 8 SC), methylation levels of the L1 promoter were determined by bisulphite pyrosequencing. RESULTS: A strong positive correlation was demonstrated between L1 transcripts and gene products that mediate de novo and constitutive DNA methylation, DNA methyltransferase (DNMT)3B, DNMT1, and methyl CpG binding protein 2 (MeCP2), in both SS MSG and lupus renal tissues. A significant negative correlation was observed between expression of L1 and lymphoid-specific helicase (LSH, encoded by HELLS) in both SS MSG and SLE kidney tissues, as well as between DNMT3A transcripts and L1 expression in SLE kidney tissues and PBMCs. Reduced levels of L1 promoter methylation along with increased DNMT3B, DNMT1, and MeCP2, but reduced LSH levels were detected in SS-low risk patients compared to both SS-lymphoma and SC. The SS-lymphoma group was also characterized by a profound decrease of MeCP2 and DNMT3B compared to SC. CONCLUSION: Our data support a contributory role of altered methylation mechanisms in the pathogenesis of systemic autoimmune disorders and related lymphoproliferative processes and suggest that LSH and DNMT3A should be investigated as candidate upstream mediators of decreased L1 promoter methylation and increased L1 expression.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Elementos de Nucleótido Esparcido Largo/genética , Lupus Eritematoso Sistémico/genética , Linfoma de Células B/genética , Glándulas Salivales/fisiología , Síndrome de Sjögren/genética , Adulto , Anciano , Células Cultivadas , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN , ADN Metiltransferasa 3A , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lupus Eritematoso Sistémico/complicaciones , Linfoma de Células B/complicaciones , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Síndrome de Sjögren/complicaciones
6.
Ann Rheum Dis ; 76(4): 740-747, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28283529

RESUMEN

OBJECTIVES: Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, and an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to suppress production of IL-17 and IL-21 by SLE T cells or human Th17 cells. METHODS: ROCK activity in peripheral blood mononuclear cells (PBMCs) from 29 patients with SLE, 31 patients with RA and 28 healthy controls was determined by ELISA. SLE T cells or in vitro-differentiated Th17 cells were treated with Y27632 (a pan-ROCK inhibitor), KD025 (a selective ROCK2 inhibitor) or simvastatin (which inhibits RhoA, a major ROCK activator). ROCK activity and IL-17 and IL-21 production were assessed. The transcriptional profile altered by ROCK inhibitors was evaluated by NanoString technology. RESULTS: ROCK activity levels were significantly higher in patients with SLE and RA than healthy controls. Th17 cells exhibited high ROCK activity that was inhibited by Y27632, KD025 or simvastatin; each also decreased IL-17 and IL-21 production by purified SLE T cells or Th17 cells. Immune profiling revealed both overlapping and distinct effects of the different ROCK inhibitors. CONCLUSIONS: ROCK activity is elevated in PBMCs from patients with SLE and RA. Production of IL-17 and IL-21 by SLE T cells or Th17 cells can furthermore be inhibited by targeting the RhoA-ROCK pathway via both non-selective and selective approaches.


Asunto(s)
Artritis Reumatoide/sangre , Interleucina-17/metabolismo , Interleucinas/metabolismo , Lupus Eritematoso Sistémico/sangre , Linfocitos T/metabolismo , Células Th17/metabolismo , Adulto , Anciano , Amidas/farmacología , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Células Cultivadas , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Transducción de Señal , Simvastatina/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimología , Células Th17/efectos de los fármacos , Células Th17/enzimología , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/metabolismo
7.
J Arthroplasty ; 32(9): 2628-2638, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28629905

RESUMEN

OBJECTIVE: This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). METHODS: A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. RESULTS: The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. CONCLUSION: This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.


Asunto(s)
Antirreumáticos/administración & dosificación , Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Atención Perioperativa/normas , Reumatología/normas , Artritis Juvenil , Artritis Psoriásica , Artritis Reumatoide , Procedimientos Quirúrgicos Electivos , Glucocorticoides/uso terapéutico , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Piperidinas , Pirimidinas , Pirroles , Enfermedades Reumáticas/tratamiento farmacológico , Espondiloartritis/tratamiento farmacológico , Espondilitis Anquilosante , Cirujanos , Estados Unidos
8.
Clin Immunol ; 172: 34-43, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27576056

RESUMEN

To gain novel insights into the immunopathogenesis of systemic lupus erythematosus we have analyzed gene expression data from isolated CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK-cell enriched peripheral blood cell fractions from patients and healthy donors. As predicted, type I interferon-inducible gene transcripts are overexpressed in all populations. Transcripts preferentially expressed in SLE CD4+ and CD8+ T cells include those associated with Tregulatory and Th17 effector cell programs, respectively, but in each case additional transcripts predicted to limit differentiation of those effector cells are detected. Evidence for involvement of the Wnt/ß-catenin pathway was observed in both B and T cell fractions, and novel transcripts were identified in each cell population. These data point to disrupted T effector cell differentiation and the Wnt/ß-catenin pathway as contributors to immune dysfunction in SLE while further supporting a central role for the type I interferon pathway in lupus.


Asunto(s)
Interferón Tipo I/inmunología , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Lupus Eritematoso Sistémico/inmunología , Vía de Señalización Wnt/inmunología , Adulto , Diferenciación Celular , Femenino , Expresión Génica , Humanos , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/genética , Persona de Mediana Edad , Adulto Joven
9.
Curr Rheumatol Rep ; 18(3): 14, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26951252

RESUMEN

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, follows a chronic disease course, punctuated by flares. Disease flares often occur without apparent cause, perhaps from progressive inherent buildup of autoimmunity. However, there is evidence that certain environmental factors may trigger the disease. These include exposure to UV light, infections, certain hormones, and drugs which may activate the innate and adaptive immune system, resulting in inflammation, cytotoxic effects, and clinical symptoms. Uncontrolled disease flares, as well as their treatment, especially with glucocorticoids, can cause significant organ damage. Tight surveillance and timely control of lupus flares with judicial use of effective treatments to adequately suppress the excessive immune system activation are required to bring about long term remission of the disease. We hope that new clinical trials will soon offer additional effective and target-specific biologic treatments for SLE.


Asunto(s)
Lupus Eritematoso Sistémico/etiología , Enfermedad Aguda , Biomarcadores/sangre , Femenino , Humanos , Infecciones/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Embarazo , Complicaciones del Embarazo , Factores de Riesgo , Terminología como Asunto , Rayos Ultravioleta/efectos adversos
11.
Trans Am Clin Climatol Assoc ; 126: 184-96, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26330673

RESUMEN

Systemic lupus erythematosus, the prototype systemic autoimmune disease, is characterized by extensive self-reactivity, inflammation, and organ system damage. Sustained production of type I interferon is seen in many patients and contributes to immune dysregulation. Disease activity fluctuates with periods of relative quiescence or effective management by immunosuppressive drugs, followed by disease flares. Tissue damage accumulates over time, with kidneys and cardiovascular system particularly affected. Identification of the underlying molecular mechanisms that precede clinical exacerbations, allowing prediction of future flare, could lead to therapeutic interventions that prevent severe disease. We generated gene expression data from a longitudinal cohort of lupus patients, some showing at least one period of severe flare and others with relatively stable disease over the period of study. Candidate predictors of future clinical flare were identified based on analysis of differentially expressed gene transcripts between the flare and non-flare groups at a time when all patients had relatively quiescent clinical disease activity. Our results suggest the hypothesis that altered regulation of genome stability and nucleic acid fidelity may be important molecular precursors of future clinical flare, generating endogenous nucleic acid triggers that engage intracellular mechanisms that mimic a chronic host response to viral infection.


Asunto(s)
Lupus Eritematoso Sistémico/etiología , Animales , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Factores de Riesgo , Resultado del Tratamiento
12.
Arthritis Rheum ; 65(6): 1592-602, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23508371

RESUMEN

OBJECTIVE: Rho-associated protein kinases (ROCKs) have been implicated in the pathogenesis of cardiovascular and renal disorders. We recently showed that ROCKs could regulate the differentiation of murine Th17 cells and the production of interleukin-17 (IL-17) and IL-21, two cytokines associated with systemic lupus erythematosus (SLE). The goal of this study was to assess ROCK activation in human Th17 cells and to evaluate ROCK activity in SLE patients. METHODS: An enzyme-linked immunosorbent assay (ELISA)-based ROCK activity assay was used to evaluate ROCK activity in human cord blood CD4+ T cells differentiated under Th0 or Th17 conditions. We then performed a cross-sectional analysis of 28 SLE patients and 25 healthy matched controls. ROCK activity in peripheral blood mononuclear cell (PBMC) lysates was determined by ELISA. Cytokine and chemokine profiles were analyzed by ELISA. RESULTS: Human cord blood CD4+ T cells differentiated under Th17 conditions expressed higher levels of ROCK activity than did CD4+ T cells stimulated under Th0 conditions. Production of IL-17 and IL-21 was inhibited by the addition of a ROCK inhibitor. SLE PBMCs expressed significantly higher levels of ROCK activity than did healthy control PBMCs (1.25 versus 0.56; P = 0.0015). Sixteen SLE patients (57%) expressed high levels of ROCK (optical density at 450 nm >1). Disease duration, lymphocyte count, and azathioprine use were shown to be significant independent predictors of ROCK activity in multivariable analyses. CONCLUSION: Consistent with previous results in the murine system, increased ROCK activation was associated with Th17 cell differentiation. Moreover, enhanced ROCK activity was observed in a subgroup of SLE patients. These data support the concept that the ROCK pathway could represent an important therapeutic target for SLE.


Asunto(s)
Linfocitos T CD4-Positivos/enzimología , Lupus Eritematoso Sistémico/enzimología , Células Th17/enzimología , Quinasas Asociadas a rho/metabolismo , Adolescente , Adulto , Anciano , Western Blotting , Técnicas de Cultivo de Célula , Estudios Transversales , Citocinas , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Th17/metabolismo , Adulto Joven
13.
Arthritis Rheumatol ; 76(7): 1002-1012, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38500017

RESUMEN

The discovery of interferon in the 1950s represents much more than the identification of the first cytokine and the key mediator of antiviral host defense. Defining the molecular nature and complexity of the type I interferon family, as well as its inducers and molecular mechanisms of action, was the work of investigators working at the highest level and producing insights of great consequence. Current knowledge of receptor-ligand interactions, cell signaling, and transcriptional regulation derives from studies of type I interferon. It is on the shoulders of the giants who produced that knowledge that others stand and have revealed critical mechanisms of the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. The design of novel therapeutics is informed by the advances in investigation of type I interferon, with the potential for important impact on patient management.


Asunto(s)
Interferón Tipo I , Lupus Eritematoso Sistémico , Animales , Humanos , Interferón Tipo I/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Transducción de Señal
14.
Clin Immunol ; 148(3): 303-12, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23566912

RESUMEN

Several studies in the last decade have highlighted the role of the type I interferon (IFN-I) pathway, and particularly interferon alpha (IFNα) in SLE pathogenesis. As a result, a multitude of potential treatments targeting IFNα have emerged in the last few years, a few of which have already completed phase II clinical trials. Some of the treatment strategies have focused on blocking IFNα or its receptor and others the plasmacytoid dendritic cell (pDC), which is the principal IFNα producing cell. In this review, we will discuss the evidence supporting a pathogenic role of IFNα and pDC in SLE, provide an update on the current status of these therapeutic strategies, and discuss the potential advantages and disadvantages of each therapeutic approach.


Asunto(s)
Interferón-alfa/antagonistas & inhibidores , Lupus Eritematoso Sistémico/tratamiento farmacológico , Animales , Células Dendríticas/fisiología , Predisposición Genética a la Enfermedad , Humanos , Interferón-alfa/fisiología , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Receptor de Interferón alfa y beta/antagonistas & inhibidores , Transducción de Señal
15.
Arthritis Rheum ; 64(4): 982-92, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22034172

RESUMEN

OBJECTIVE: To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. METHODS: We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Felty's syndrome (FS), and antineutrophil cytoplasmic antibody-associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro-deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects. RESULTS: Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients. CONCLUSION: Circulating autoantibodies in FS are preferentially directed against PAD-4-deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS.


Asunto(s)
Autoanticuerpos/inmunología , Síndrome de Felty/inmunología , Histonas/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Artritis Reumatoide/inmunología , Autoantígenos/inmunología , Femenino , Humanos , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología
16.
Arthritis Rheum ; 64(12): 4040-7, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22932861

RESUMEN

OBJECTIVE: To determine the value of cell-bound complement activation products in combination with antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), and anti-mutated citrullinated vimentin antibody (anti-MCV) for the diagnosis of systemic lupus erythematosus (SLE). METHODS: This was a multicenter cross-sectional study in which 593 subjects were enrolled (210 SLE patients, 178 patients with other rheumatic diseases, and 205 healthy subjects). Complement receptor 1 levels on erythrocytes (ECR1) together with complement C4d levels on erythrocytes (EC4d), platelets (PC4d), and B cells (BC4d) were determined using fluorescence-activated cell sorting. Serologic markers were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed using area under the curve (AUC), logistic regression, and calculations of diagnostic sensitivity and specificity. RESULTS: Anti-dsDNA was an insensitive (30%) but specific (>95%) marker for SLE. Levels of EC4d, BC4d, and PC4d were several times higher, and levels of ECR1 lower, in SLE patients compared to patients with other rheumatic diseases and healthy subjects. Among 523 anti-dsDNA-negative subjects, multivariate logistic regression analysis revealed that SLE was associated with ANA positivity (≥20 units), anti-MCV negativity (≤70 units), and elevated levels of both EC4d and BC4d (AUC 0.918, P < 0.001). A positive index score corresponding to the weighted sum of these 4 markers correctly categorized 72% of SLE patients. Specificity in relation to patients with other rheumatic diseases and healthy controls was >90%. The combination of anti-dsDNA and index score positivity yielded 80% sensitivity for SLE and 87% specificity against other rheumatic diseases. CONCLUSION: An assay panel combining anti-dsDNA, ANA, anti-MCV, EC4d, and BC4d is sensitive and specific for the diagnosis of SLE.


Asunto(s)
Linfocitos B/inmunología , Plaquetas/inmunología , Eritrocitos/inmunología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Fragmentos de Péptidos/sangre , Receptores de Complemento/sangre , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antiidiotipos/sangre , Anticuerpos Antinucleares/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Activación de Complemento/fisiología , Complemento C4b , Estudios Transversales , ADN/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Sensibilidad y Especificidad , Vimentina/sangre
17.
J Immunol ; 187(3): 1298-303, 2011 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-21705624

RESUMEN

Increased IFN-α signaling is a heritable risk factor for systemic lupus erythematosus (SLE). IFN induced with helicase C domain 1 (IFIH1) is a cytoplasmic dsRNA sensor that activates IFN-α pathway signaling. We studied the impact of the autoimmune-disease-associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism upon IFN-α signaling in SLE patients in vivo. We studied 563 SLE patients (278 African-American, 179 European-American, and 106 Hispanic-American). Logistic regression models were used to detect genetic associations with autoantibody traits, and multiple linear regression was used to analyze IFN-α-induced gene expression in PBMCs in the context of serum IFN-α in the same blood sample. We found that the rs1990760 T allele was associated with anti-dsDNA Abs across all of the studied ancestral backgrounds (meta-analysis odds ratio = 1.34, p = 0.026). This allele also was associated with lower serum IFN-α levels in subjects who had anti-dsDNA Abs (p = 0.0026). When we studied simultaneous serum and PBMC samples from SLE patients, we found that the IFIH1 rs1990760 T allele was associated with increased IFN-induced gene expression in PBMCs in response to a given amount of serum IFN-α in anti-dsDNA-positive patients. This effect was independent of the STAT4 genotype, which modulates sensitivity to IFN-α in a similar way. Thus, the IFIH1 rs1990760 T allele was associated with dsDNA Abs, and in patients with anti-dsDNA Abs this risk allele increased sensitivity to IFN-α signaling. These studies suggest a role for the IFIH1 risk allele in SLE in vivo.


Asunto(s)
Autoanticuerpos/sangre , ARN Helicasas DEAD-box/fisiología , Variación Genética/inmunología , Interferón-alfa/fisiología , Lupus Eritematoso Sistémico/enzimología , Lupus Eritematoso Sistémico/inmunología , Alelos , Autoanticuerpos/biosíntesis , Línea Celular , ARN Helicasas DEAD-box/genética , ADN/inmunología , Humanos , Helicasa Inducida por Interferón IFIH1 , Interferón-alfa/sangre , Interferón-alfa/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple/inmunología , Factores de Riesgo , Transducción de Señal/genética , Transducción de Señal/inmunología
18.
HSS J ; 19(2): 180-186, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37051614

RESUMEN

Background: Immunosuppressive agents inhibit COVID-19 vaccine antibody (Ab) responses in patients with systemic rheumatic diseases. Rituximab may fully block Ab responses when B cells become undetected. The effect of detected but low number of B cells due to treatment with a B-cell agent (belimumab and/or rituximab) has not been established. Purpose: We sought to examine whether there is an association between a low number of B cells due to treatment with belimumab and/or rituximab and impaired primary COVID-19 vaccination spike Ab responses in patients with systemic rheumatic diseases. Methods: We retrospectively examined Ab responses to COVID-19 vaccinations, especially in relation to B-cell counts after treatment with belimumab and/or rituximab, in 58 patients with systemic rheumatic diseases: 22 on and 36 not on B-cell agents. We used Kruskal-Wallis and Mann-Whitney U tests for comparison of Ab values between the groups and Fisher exact test for relative risk calculations. Results: Median (interquartile range) postvaccination Ab responses were lower in patients on versus those not on B-cell agents: 3.91 (0.77-20.00) versus 20.00 (14.32-20.00), respectively. Among patients on belimumab and/or rituximab, Ab responses of less than 25% of the assay's upper limit were exclusively observed in those with B-cell counts lower than 40/µL. Patients with B-cell counts lower than 40/µL exhibit a relative risk of 6.092 (95% CI: 2.75-14.24) for Ab responses of less than 25% of the upper limit compared with patients not on B-cell agents. This relative risk remained significant, even after excluding patients with undetected B cells. Conclusion: This retrospective study found an association between low B-cell counts (less than 40/µL) and decreased Ab responses to primary COVID-19 vaccination in patients with systemic rheumatic diseases treated with belimumab and/or rituximab. Despite the small number of patients studied, these findings add to the accumulating evidence on the importance of B-cell count in predicting spike Ab responses to COVID-19 vaccination.

19.
Soc Work Health Care ; 51(7): 652-60, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22905980

RESUMEN

The complexity of systemic lupus erythematosus (SLE) and its psychosocial impact creates management challenges that require a multidisciplinary team approach for optimal patient care and outcomes. This article provides a brief report on current lupus-related research studies at the Mary Kirkland Center for Lupus Care at Hospital for Special Surgery. Studies and their social work implications highlight a comprehensive, integrated model for research, education, and patient care emphasizing interdisciplinary collaboration. Both basic science and clinical research are discussed, with a focus on the role of social workers as an integral part of the health care team in providing assessments and interventions and as support for patients in research studies.


Asunto(s)
Investigación sobre Servicios de Salud/organización & administración , Lupus Eritematoso Sistémico/psicología , Grupo de Atención al Paciente/organización & administración , Servicio Social/organización & administración , Biomarcadores , Progresión de la Enfermedad , Femenino , Predicción , Investigación sobre Servicios de Salud/métodos , Hospitales de Enfermedades Crónicas , Humanos , Comunicación Interdisciplinaria , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/terapia , Ciudad de Nueva York , Grupo de Atención al Paciente/normas , Cooperación del Paciente/psicología , Cooperación del Paciente/estadística & datos numéricos , Embarazo , Complicaciones del Embarazo/diagnóstico , Medición de Riesgo , Servicio Social/normas , Nivel de Atención
20.
Arthritis Care Res (Hoboken) ; 74(4): 656-664, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-33171010

RESUMEN

OBJECTIVE: The risk of thrombotic events is elevated in patients with systemic lupus erythematosus (SLE) compared to the general population and has been attributed to both systemic inflammation and to the presence of antiphospholipid antibodies (aPLs). Our objective was to examine differences in aPL prevalence in White and African American patients with SLE and venous thromboembolic (VTE) events, and to compare inflammatory markers at the time of a VTE event. METHODS: Records of White and African American patients with SLE and VTE events were retrieved from a rheumatology practice based at an academic hospital. A clinically significant aPL profile was defined as anti-cardiolipin IgG/IgM and/or anti-ß2 -glycoprotein I IgG/IgM ≥40 units, and/or positive lupus anticoagulant ≥1.3. Logistic regression was used to determine predictors of a clinically significant aPL profile. RESULTS: Ninety-seven patients fulfilled American College of Rheumatology and/or 2012 Systemic Lupus Erythematosus International Collaborating Clinics classification criteria for SLE, had a history of VTE events, and had available aPL tests (59 White and 38 African American patients). African American patients were 66% less likely (95% confidence interval 0.12-0.96; P = 0.04) to have a clinically significant aPL profile compared to White patients in multivariable regression. Triple positivity was most frequent among White patients, while 7 of 8 African American patients had a positive lupus anticoagulant test. At the time of a VTE event, African American patients had significantly higher levels of anti-double-stranded DNA (P = 0.02), lower hemoglobin (P = 0.01), and higher erythrocyte sedimentation rate (P = 0.008). CONCLUSION: Among patients with SLE and VTE events, African American patients were less likely to have a clinically significant aPL profile compared to White patients, indicating that a negative aPL profile in African American patients does not decrease VTE risk.


Asunto(s)
Síndrome Antifosfolípido , Lupus Eritematoso Sistémico , Tromboembolia Venosa , Negro o Afroamericano , Anticuerpos Anticardiolipina , Anticuerpos Antifosfolípidos , Autoanticuerpos , Humanos , Inmunoglobulina G , Inmunoglobulina M , Inhibidor de Coagulación del Lupus , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/epidemiología , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología
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