Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 75
Filtrar
2.
Curr Opin Rheumatol ; 33(3): 221-232, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33741807

RESUMO

PURPOSE OF REVIEW: Although mycophenolate mofetil (MMF) has been used successfully to treat a myriad of autoimmune diseases, its complex pharmacokinetics make it difficult to determine the true drug exposure for an individual patient. This review summarizes the body of literature focused on the gold standard measurement of the area under the curve (AUC) of mycophenolic acid (MPA), the active metabolite of MMF. RECENT FINDINGS: Fixed dosing of MMF leads to highly variable drug exposure. Retrospective series have reported improved clinical outcomes when a minimum AUC value from 0 to 12 h (AUC0-12h) ≥30 mg h/l is achieved. MPA levels are affected by various drug interactions, hypoalbuminemia, and renal insufficiency and the measurement of free rather than total MPA levels is prudent in some situations. A limited number of studies employing prospective dose adjustment of MMF based on AUC0-12h measurements have yielded mixed results. SUMMARY: Given the wide range of MPA AUC encountered in autoimmune diseases, dose adjustments of MMF based on AUC rather than fixed dosing of MMF should be considered in both clinical practice and clinical trials. Limited sampling strategies have been proposed to improve clinical feasibility of measurements, but a standard is yet to be defined.

3.
Arthritis Rheumatol ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33474834

RESUMO

OBJECTIVE: Epidemiologic data for systemic lupus erythematosus (SLE) is limited, particularly for racial/ethnic subpopulations in the United States (U.S.). Leveraging data from the Centers for Disease Control and Prevention (CDC) National Lupus Registry network of population-based SLE registries, a meta-analysis estimating U.S. SLE prevalence was performed. METHODS: The CDC National Lupus Registry network included four registries in unique states and a fifth in the Indian Health Service (IHS). All registries used the 1997 revised American College of Rheumatology (ACR) classification criteria for the SLE case definition. Case finding spanned either 2002-2004 or 2007-2009. A random effects model was employed given heterogeneity across sites. Applying sex/race-stratified estimates to the 2018 Census population, an estimate for the number of SLE cases in the U.S. was generated. RESULTS: 5,417 cases fulfilled the ACR SLE classification criteria. Pooled prevalence from the four state-specific registries was 72.8/100,000 (95%CI:65.3,81.0), 9 times higher for females than males (128.7 vs 14.6), and highest among Black females (230.9), followed by Hispanic (120.7), white (84.7) and Asian/Pacific Islander females (84.4). Male prevalence was highest in Black males (26.7) followed by Hispanic (18.0), Asian/Pacific Islander (11.2), and white males (8.9). The American Indian/Alaska Native had the highest race-specific SLE estimates for females (270.6/100,000) and males (53.8/100,000). In 2018, 204,295 persons (95% CI:160,902,261,725) in the U.S. fulfilled ACR SLE classification criteria. CONCLUSIONS: A coordinated network of population-based SLE registries provided more accurate estimates for SLE prevalence and numbers affected in the U.S.

4.
JCI Insight ; 5(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33108347

RESUMO

Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus neutrophils over 4 years of follow-up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are partly determined by ancestry-associated genetic variations and are highly stable over time. DNA methylation levels in 2 CpG sites correlated significantly with changes in lupus disease activity. Progressive demethylation in SNX18 was observed with increasing disease activity in African American patients. Importantly, demethylation of a CpG site located within GALNT18 was associated with the development of active lupus nephritis. Differentially methylated genes between African American and European American lupus patients include type I IFN-response genes such as IRF7 and IFI44, and genes related to the NF-κB pathway. TREML4, which plays a vital role in TLR signaling, was hypomethylated in African American patients and demonstrated a strong cis-methylation quantitative trait loci (cis-meQTL) effect among 8855 cis-meQTL associations identified in our study.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32741110

RESUMO

BACKGROUND: Medication access and adherence are important determinants of health outcomes. We investigated factors associated with access and cost-related non-adherence to prescriptions in a population-based cohort of systemic lupus erythematosus (SLE) patients and controls. METHODS: Detailed sociodemographic and prescription data were collected by structured interview in 2014-2015 from participants in the Michigan Lupus Epidemiology & Surveillance (MILES) Cohort. We compared access between cases and frequency-matched controls and examined associated factors in separate multivariable logistic regression models. RESULTS: 654 participants (462 SLE cases, 192 controls) completed the baseline visit; 584 (89%) were female, 285 (44%) black, and mean age was 53 years. SLE cases and controls reported similar frequencies of being unable to access prescribed medications (12.1% vs 9.4%, respectively; p=NS). SLE patients were twice as likely as controls to report cost-related prescription non-adherence in the preceding 12 months to save money (21.7% vs 10.4%; p=0.001), but also more likely to ask their doctor for lower cost alternatives (23.8% vs 15.6%, p=0.02). Disparities were found in association with income, race and health insurance status, but main findings persisted after adjusting for these and other variables in multivariable models. CONCLUSION: SLE patients were more likely than controls from the general population to report cost-related prescription non-adherence, including skipping doses, taking less medicine and delaying filling prescriptions, yet less than 1 in 4 patients asked providers for lower cost medications. Consideration of medication costs in patient decision-making could provide a meaningful avenue for improving access and adherence to medications.

6.
Arthritis Care Res (Hoboken) ; 72(7): 874-881, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31074595

RESUMO

OBJECTIVE: To examine associations between dietary intake of omega-3 (n-3; generally antiinflammatory) and omega-6 (n-6; generally proinflammatory) fatty acids and patient-reported outcomes in systemic lupus erythematosus (SLE). METHODS: This study was based on the population-based Michigan Lupus Epidemiology and Surveillance cohort. Estimates of n-3 and n-6 intake were derived from Diet History Questionnaire II items (past year with portion size version). Patient-reported outcomes included self-reported lupus activity (Systemic Lupus Activity Questionnaire [SLAQ]). Multivariable regression, adjusted for age, sex, race, and body mass index, was used to assess associations between absolute intake of n-3 and n-6, as well as the n-6:n-3 ratio, and patient-reported outcomes. RESULTS: Among 456 SLE cases, 425 (93.2%) were female, 207 (45.4%) were African American, and the mean ± SD age was 52.9 ± 12.3 years. Controlling for potential confounders, the average SLAQ score was significantly higher by 0.3 points (95% confidence interval [95% CI] 0.1, 0.6; P = 0.013) with each unit increase of the n-6:n-3 ratio. Both lupus activity and Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance scores were lower with each 1-gram/1,000 kcal increase of n-3 fatty acids (SLAQ regression coefficient ß = -0.8 [95% CI -1.6, 0.0]; P = 0.055; PROMIS sleep ß = -1.1 [95% CI -2.0, -0.2]; P = 0.017). Higher n-3 intakes were nonsignificantly associated with lower levels of depressive symptoms and comorbid fibromyalgia, and with higher quality of life, whereas results for the n6:n3 ratio trended in the opposite direction. CONCLUSION: This population-based study suggests that higher dietary intake of n-3 fatty acids and lower n-6:n-3 ratios are favorably associated with patient-reported outcomes in SLE, particularly self-reported lupus activity and sleep quality.


Assuntos
Dieta , Ácidos Graxos Ômega-3 , Ácidos Graxos Ômega-6 , Lúpus Eritematoso Sistêmico , Adulto , Idoso , Estudos de Coortes , Inquéritos sobre Dietas , Feminino , Humanos , Masculino , Michigan , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida
7.
Artigo em Inglês | MEDLINE | ID: mdl-31866283

RESUMO

Administration of cyclophosphamide (CYC), an alkylating agent used to treat malignancies and severe rheumatic diseases, creates a risk of ovarian insufficiency that is related to the intensity and duration of therapy and the age of the patient. To preserve reproductive capacity in the appropriate clinical setting, oocyte, embryo, and/or ovarian tissue cryopreservation are recommended. Medical protection with depot gonadotropin-releasing hormone agonists (GNRHa) has emerged as a potential means to preserve both fertility and ovarian function through the suppression of ovarian activity during treatment with alkylators. We review the trials of GNRHa for ovarian protection in both cancer and rheumatic disease patients. Trials in cancer patients receiving CYC alone, or in combination with other gonadotoxic agents that have employed several different GNRHa have yielded mixed results. Trials in lupus patients receiving lower doses of CYC alone utilizing depot leuprolide acetate have tended to show favorable results.


Assuntos
Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Hormônio Liberador de Gonadotropina/administração & dosagem , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Insuficiência Ovariana Primária/prevenção & controle , Alquilantes/administração & dosagem , Alquilantes/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Feminino , Fármacos para a Fertilidade Feminina , Humanos , Leuprolida , Lúpus Eritematoso Sistêmico/complicações , Insuficiência Ovariana Primária/etiologia
8.
MMWR Morb Mortal Wkly Rep ; 68(38): 819-824, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31557148

RESUMO

Rheumatic diseases are a leading cause of chronic, noncancer pain. Systemic lupus erythematosus (SLE) is a chronic autoimmune rheumatic disease characterized by periodic flares that can result in irreversible target organ damage, including end-stage renal disease. Both intermittent and chronic musculoskeletal pain, as well as fibromyalgia (considered a centralized pain disorder due to dysregulation of pain processing in the central nervous system), are common in SLE. Opioids are generally not indicated for long-term management of musculoskeletal pain or centralized pain (fibromyalgia) because of lack of efficacy, safety issues ranging from adverse medical effects to overdose, and risk for addiction (1,2). In this study of 462 patients with SLE from the population-based Michigan Lupus Epidemiology and Surveillance (MILES) Cohort and 192 frequency-matched persons without SLE, nearly one third (31%) of SLE patients were using prescription opioids during the study period (2014-2015), compared with 8% of persons without SLE (p<0.001). Among the SLE patients using opioids, 97 (68%) were using them for >1 year, and 31 (22%) were concomitantly on two or more opioid medications. Among SLE patients, those using the emergency department (ED) were approximately twice as likely to use prescription opioids (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.6; p = 0.004). In SLE, the combined contributions of underlying disease and adverse effects of immunosuppressive and glucocorticoid therapies already put patients at higher risk for some known adverse effects attributed to long-term opioid use. Addressing the widespread and long-term use of opioid therapy in SLE will require strategies aimed at preventing opioid initiation, tapering and discontinuation of opioids among patients who are not achieving treatment goals of reduced pain and increased function, and consideration of nonopioid pain management strategies.


Assuntos
Analgésicos Opioides/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Vigilância da População , Adulto , Idoso , Estudos de Coortes , Serviço Hospitalar de Emergência , Feminino , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Michigan/epidemiologia , Pessoa de Meia-Idade , Manejo da Dor/métodos , Risco
9.
BMJ Case Rep ; 12(7)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31345830

RESUMO

A man in his 70s with known systemic lupus erythematosus (SLE) was admitted with confusion, worsening proteinuria and cutaneous vasculitis despite adherence to his home immunosuppressive regimen. Admission laboratories were consistent with active lupus. Despite treatment with pulse-dose glucocorticoids and intravenous immunoglobulin, he developed worsening mental status and meningeal signs. Investigations revealed cerebrospinal fluid (CSF) neutrophilic and plasmacytic pleocytosis and negative cultures. Empiric treatment for SLE flare with potential neuropsychiatric involvement was continued while workup for altered mental status was ongoing. Ultimately, West Nile encephalitis was diagnosed by CSF serologies, and steroids were tapered. Altered mental status in a patient with SLE has a broad differential, and primary neuropsychiatric SLE should be considered only after exclusion of secondary causes. Although evidence of end-organ SLE activity usually lends support to a neuropsychiatric SLE diagnosis, in this case, serological and clinical evidence of SLE activity may have been triggered by acute viral infection.


Assuntos
Confusão/virologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/virologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Proteinúria/virologia , Febre do Nilo Ocidental/diagnóstico , Vírus do Nilo Ocidental/isolamento & purificação , Idoso , Diagnóstico Diferencial , Eletroencefalografia , Evolução Fatal , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Punção Espinal , Febre do Nilo Ocidental/fisiopatologia , Febre do Nilo Ocidental/terapia
10.
Curr Opin Rheumatol ; 31(3): 213-222, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30920453

RESUMO

PURPOSE OF REVIEW: Medical therapies for the treatment of immune thrombocytopenia (ITP) complicating SLE are increasingly being investigated as alternatives to splenectomy and IVIG. The purpose of this review is to highlight the therapies that are utilized in the treatment of primary ITP and ITP secondary to lupus. RECENT FINDINGS: Corticosteroids are still the standard initial treatment of ITP, with the addition of IVIG when a rapid response is needed. There are few studies dedicated to assessing the efficacy of disease-modifying antirheumatic (DMARD), biologic, and nonimmunosuppressive agents as treatment for lupus thrombocytopenia/lupus ITP. Rituximab and thrombopoeitin mimetics have been the most extensively studied therapies for primary ITP in recent years. Results of trials show adequate initial responses; however, the duration of therapy and sustainability of responses are variable. Splenectomy is less often utilized. SUMMARY: Although corticosteroids, intravenous immunoglobulin and splenectomy have proven to be effective measures to treat immune thrombocytopenia, newer studies have demonstrated positive outcomes of immunosuppressives and thrombopoeitin mimetics. In most cases, the reported duration of therapy was not prolonged. More studies are needed to fully assess the effect of medical therapy in lupus ITP and to determine how long to continue maintenance therapy.


Assuntos
Corticosteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Humanos , Púrpura Trombocitopênica Idiopática/cirurgia , Rituximab/uso terapêutico , Esplenectomia , Resultado do Tratamento
11.
Arthritis Rheumatol ; 71(7): 1125-1134, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30771238

RESUMO

OBJECTIVE: To investigate the long-term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE. METHODS: The study was designed as a multicenter, open-label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals). RESULTS: Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline. CONCLUSION: This study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long-term disease control.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Quimioterapia Combinada , Duração da Terapia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Infecções/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Padrão de Cuidado , Resultado do Tratamento
12.
Curr Opin Rheumatol ; 31(3): 231-240, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30747734

RESUMO

PURPOSE OF REVIEW: Although antiphospholipid syndrome (APS) is best known for conveying increased risk of thrombotic events and pregnancy morbidity, thrombocytopenia is also recognized as a common association. In this review, we will explore the relationship between thrombocytopenia and APS, highlighting our evolving understanding - and persistent knowledge gaps - through clinically oriented questions and answers. RECENT FINDINGS: A history of thrombocytopenia likely portends a more severe APS phenotype (including increased risk of thrombosis). Although the pathophysiology underlying thrombocytopenia in APS has yet to be definitively revealed, mechanisms that play a role (at least in subsets of patients) include: immune thrombocytopenic purpura/ITP-like autoantibodies against platelet glycoproteins; antiphospholipid antibody (aPL)-mediated platelet activation and consumption; and potentially life threatening thrombotic microangiopathy. Although thrombocytopenia is often 'mild' in APS (and therefore, may not require specific therapy), there are causes of acute-onset thrombocytopenia that mandate emergent work-up and treatment. When APS-related thrombocytopenia does require therapy, the approach must be individualized (requiring an understanding of pathophysiology in the particular APS patient). For patients with ITP-like disease, rituximab is emerging as a popular approach to treatment; in contrast, there are hints that thrombopoietin mimetics may be associated with elevated thrombotic risk. SUMMARY: Thrombocytopenia is common in APS, and is likely associated with more severe disease. Improved understanding of thrombocytopenia in APS has the potential to improve risk stratification, reveal novel aspects of APS pathophysiology, and lead to treatments that are more individualized and holistic.


Assuntos
Anticorpos Antifosfolipídeos , Síndrome Antifosfolipídica/complicações , Trombocitopenia/complicações , Síndrome Antifosfolipídica/imunologia , Feminino , Humanos , Masculino , Gravidez , Trombocitopenia/imunologia
13.
Ann Rheum Dis ; 78(5): 634-640, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30692164

RESUMO

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined.


Assuntos
Técnicas de Apoio para a Decisão , Lúpus Eritematoso Sistêmico/classificação , Reumatologia/normas , Consenso , Humanos , Reprodutibilidade dos Testes , Reumatologia/métodos
14.
Clin J Am Soc Nephrol ; 13(2): 251-257, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29371340

RESUMO

BACKGROUND AND OBJECTIVES: The significance of persistent hematuria or proteinuria in patients with ANCA-associated vasculitis who are otherwise in clinical remission is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis was conducted using participants enrolled in two randomized, placebo-controlled clinical trials who had active GN due to ANCA-associated vasculitis, had positive ANCA, and achieved remission by month 6. Dipstick and microscopic urinalyses were performed at each visit. Persistent hematuria or proteinuria for at least 6 months and the cumulative duration of hematuria were examined. Renal relapse was defined as new or worsening red blood cell casts and/or worsening kidney function according to the Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis. RESULTS: There were 149 patients included in this study: 42% had persistent hematuria, and 43% had persistent proteinuria beyond 6 months. Persistent hematuria was associated with a significantly higher risk of relapse, even after adjusting for potential confounders (subdistribution hazard ratio, 3.99; 95% confidence interval, 1.20 to 13.25; P=0.02); persistent proteinuria was not associated with renal relapse (subdistribution hazard ratio, 1.44; 95% confidence interval, 0.47 to 4.42; P=0.53). Furthermore, greater cumulative duration of hematuria was significantly associated with a higher risk of renal relapse (adjusted subdistribution hazard ratio, 1.08 per each month; 95% confidence interval, 1.03 to 1.12; P<0.01). The median time to renal relapse was 22 months. CONCLUSIONS: In patients with ANCA-associated vasculitis and kidney involvement who achieve remission after induction therapy, the presence of persistent hematuria, but not proteinuria, is a significant predictor of future renal relapse.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/urina , Glomerulonefrite/urina , Hematúria/urina , Proteinúria/urina , Urinálise , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Biomarcadores/urina , Progressão da Doença , Etanercepte/uso terapêutico , Feminino , Glomerulonefrite/diagnóstico , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Hematúria/diagnóstico , Hematúria/tratamento farmacológico , Hematúria/imunologia , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/imunologia , Falência Renal Crônica/urina , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteinúria/diagnóstico , Proteinúria/tratamento farmacológico , Proteinúria/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fitas Reagentes , Recidiva , Indução de Remissão , Medição de Risco , Fatores de Risco , Rituximab/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Urinálise/instrumentação
15.
J Autoimmun ; 86: 19-28, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29066026

RESUMO

OBJECTIVE: The goal of this study was to comprehensively characterize CD4+CD28+ T cells overexpressing CD11a and KIR genes, and examine the relationship between this T cell subset, genetic risk, and disease activity in lupus. METHODS: The size of the CD4+CD28+KIR+CD11ahi T cell subset was determined by flow cytometry, and total genetic risk for lupus was calculated in 105 female patients using 43 confirmed genetic susceptibility loci. Primary CD4+CD28+KIR+CD11ahi T cells were isolated from lupus patients or were induced from healthy individuals using 5-azacytidine. Genome-wide DNA methylation was analyzed using an array-based approach, and the transcriptome was assessed by RNA sequencing. Transcripts in the CDR3 region were used to assess the TCR repertoire. Chromatin accessibility was determined using ATAC-seq. RESULTS: A total of 31,019 differentially methylated sites were identified in induced KIR+CD11ahi T cells with >99% being hypomethylated. RNA sequencing revealed a clear pro-inflammatory transcriptional profile. TCR repertoire analysis suggests less clonotype diversity in KIR+CD11ahi compared to autologous KIR-CD11alow T cells. Similarly, primary KIR+CD11ahi T cells isolated from lupus patients were hypomethylated and characterized by a pro-inflammatory chromatin structure. We show that the genetic risk for lupus was significantly higher in African-American compared to European-American lupus patients. The demethylated CD4+CD28+KIR+CD11ahi T cell subset size was a better predictor of disease activity in young (age ≤ 40) European-American patients independent of genetic risk. CONCLUSION: CD4+CD28+KIR+CD11ahi T cells are demethylated and characterized by pro-inflammatory epigenetic and transcriptional profiles in lupus. Eliminating these cells or blocking their pro-inflammatory characteristics might present a novel therapeutic approach for lupus.


Assuntos
Afro-Americanos , Inflamação/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Antígeno CD11a/metabolismo , Antígenos CD28/metabolismo , Antígenos CD4/metabolismo , Células Cultivadas , Metilação de DNA , Progressão da Doença , Epigênese Genética , Feminino , Perfil Genético , Humanos , Imunofenotipagem , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Receptores KIR/metabolismo , Risco , Análise de Sequência de RNA , Estados Unidos/epidemiologia
16.
Curr Opin Rheumatol ; 29(3): 248-253, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28306595

RESUMO

PURPOSE OF REVIEW: The antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitides are a group of rare systemic diseases. The past several years have seen major therapeutic advances in the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The success rate in induction of remission is high, but reducing the high incidence of relapses remains a therapeutic challenge. RECENT FINDINGS: Studies have shown no improvement in relapse rates in GPA and MPA over the past 2 decades. This has prompted a recent focus on therapeutic strategies to maintain remission in these relapsing diseases. Low-dose rituximab (RTX) at fixed intervals has been shown superior to azathioprine for maintenance of remission. Despite this advance, longer follow-up periods have shown late-stage relapses with withdrawal of therapy suggesting a possible need for longer treatment regimens. Evaluation of prognostic indicators is also helpful in stratifying patients who might be more likely to relapse or to respond to a particular therapy. SUMMARY: Results from recent research have significantly advanced our approach to prevention of relapses in GPA and MPA. Newer maintenance agents have shown benefit in maintenance of remission and relapse-free survival.


Assuntos
Azatioprina/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Poliangiite Microscópica/tratamento farmacológico , Rituximab/uso terapêutico , Anticorpos Monoclonais Murinos/uso terapêutico , Granulomatose com Poliangiite/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Poliangiite Microscópica/imunologia , Prognóstico , Indução de Remissão
17.
Curr Opin Rheumatol ; 29(3): 228-233, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28240614

RESUMO

PURPOSE OF REVIEW: There are no established guidelines for evaluating and treating hypogammaglobulinemia in patients with rheumatic disease who receive B-cell depleting agents. The purpose of this article is to review findings in the work-up and treatment of common variable immunodeficiency (CVID) that can guide our evaluation of patients with autoimmune disease who develop hypogammaglobulinemia after rituximab/B-cell depleting therapy. RECENT FINDINGS: Infection rates are higher in rheumatic disease patients who develop hypogammaglobulinemia than those who do not. However, not all patients who develop hypogammaglobulinemia are at increased risk of developing infection after B-cell depleting therapy. Recent consensus statements have helped refine the diagnosis of impaired immune responses in patients with CVID, and can provide guidance for the diagnostic work-up and therapeutic decision making for patients with secondary drug induced hypogammaglobulinemia. SUMMARY: Based on findings in studies of CVID, assessment of vaccine response in patients with hypogammglogulinemia after rituximab therapy in the setting of recurrent infections can help predict propensity for infection and thus guide decision making with regards to intravenous immunoglobulin supplementation and retreatment with rituximab.


Assuntos
Agamaglobulinemia , Linfócitos B/imunologia , Imunidade Celular , Rituximab/administração & dosagem , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/imunologia , Humanos , Fatores Imunológicos/administração & dosagem
18.
Ann Rheum Dis ; 76(2): 450-457, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27432357

RESUMO

OBJECTIVES: Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS. METHODS: We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes. RESULTS: Endothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody. CONCLUSIONS: We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.


Assuntos
Síndrome Antifosfolipídica/imunologia , Diferenciação Celular/fisiologia , Células Progenitoras Endoteliais/fisiologia , Interferon-alfa/imunologia , Leucócitos Mononucleares/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/farmacologia , Síndrome Antifosfolipídica/fisiopatologia , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Células Progenitoras Endoteliais/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Interferon Tipo I/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Interferon alfa e beta/antagonistas & inibidores , Adulto Jovem
19.
Arthritis Rheumatol ; 68(9): 2200-9, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27111767

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is a relapsing autoimmune disease that affects multiple organ systems. T cells play an important role in the pathogenesis of lupus; however, early T cell events triggering disease flares are incompletely understood. This study was undertaken to examine DNA methylation in naive CD4+ T cells from lupus patients to determine if epigenetic remodeling in CD4+ T cells is an early event in lupus flares. METHODS: A total of 74 lupus patients with an SLE Disease Activity Index score of 0-18 were included. Naive CD4+ T cells were isolated from peripheral blood samples, and DNA was extracted for genome-wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcription activity using RNA sequencing and microRNA arrays. RESULTS: We demonstrated that naive CD4+ T cells in lupus undergo an epigenetic proinflammatory shift, implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without changes in expression of the corresponding genes, poises naive CD4+ T cells for Th2, Th17, and follicular helper T cell immune responses, and opposes inhibitory transforming growth factor ß signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might play an important role in shifting the epigenetic landscape, with increased disease activity in lupus naive CD4+ T cells. Further, the expression of microRNA-26a, which is sensitive to glucose availability and targets EZH2, was negatively correlated with disease activity in lupus patients. CONCLUSION: An epigenetic landscape shift in naive CD4+ T cells that favors T cell activation and non-Th1 immune responses predates transcription activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation.


Assuntos
Linfócitos T CD4-Positivos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Ativação Linfocitária/genética , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Adulto , Idoso , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
20.
Curr Opin Rheumatol ; 28(3): 218-27, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26927441

RESUMO

PURPOSE OF REVIEW: Catastrophic antiphospholipid syndrome (CAPS) is a severe manifestation of antiphospholipid syndrome (APS). Although affecting only 1% of patients with APS, the condition is frequently fatal if not recognized and treated early. Here, we will review the current approach to diagnosis and treatment of CAPS. RECENT FINDINGS: Data from the international 'CAPS registry', spearheaded by the European Forum on Antiphospholipid Antibodies, have improved our understanding of at-risk patients, typical clinical features, and precipitating diagnoses. Current guidelines also continue to support the role of anticoagulants and glucocorticoids as foundation therapy in all patients. Finally, new basic science and case series suggest that novel therapies, such as rituximab and eculizumab, warrant further study. SUMMARY: Attention to associated diagnoses, such as infection and systemic lupus erythematosus (SLE), is critical at the time of diagnosis. All patients should be treated with anticoagulants, corticosteroids, and possibly plasma exchange. In patients with SLE, cyclophosphamide should be considered. In refractory or relapsing cases, new therapies, such as rituximab and possibly eculizumab, may be options, but need further study.


Assuntos
Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/terapia , Doença Catastrófica/terapia , Gerenciamento Clínico , Glucocorticoides/uso terapêutico , Troca Plasmática/métodos , Guias de Prática Clínica como Assunto , Humanos , Recidiva
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...