RESUMO
OBJECTIVE: Disparities in pregnancy outcomes among women with SLE remain understudied, with few available racially diverse datasets. We sought to identify disparities between Black and White women in pregnancy outcomes within academic institutions in the United States. METHODS: Using the Common Data Model electronic medical record (EMR)-based datasets within the Carolinas Collaborative, we identified women with pregnancy delivery data (2014-2019) and ≥1 SLE International Classification of Diseases 9 or 10 code (ICD9/10) code. From this dataset, we identified four cohorts of SLE pregnancies, three based on EMR-based algorithms and one confirmed with chart review. We compared the pregnancy outcomes identified in each of these cohorts for Black and White women. RESULTS: Of 172 pregnancies in women with ≥1 SLE ICD9/10 code, 49% had confirmed SLE. Adverse pregnancy outcomes occurred in 40% of pregnancies in women with ≥1 ICD9/10 SLE code and 52% of pregnancies with confirmed SLE. SLE was frequently over-diagnosed in women who were White, resulting in 40-75% lower rates of adverse pregnancy outcomes in EMR-derived vs confirmed SLE cohorts. Over-diagnosis was less common for Black women with pregnancy outcomes 12-20% lower in EMR-derived vs confirmed SLE cohorts. Black women had higher rates of adverse pregnancy outcomes than White women in the EMR-derived, but not the confirmed cohorts. CONCLUSION: EMR-derived cohorts of pregnancies in women who are Black, but not White, provided accurate estimations of pregnancy outcomes. The data from the confirmed SLE pregnancies suggest that all women with SLE, regardless of race, referred to academic centres remain at very high risk for adverse pregnancy outcome.
Assuntos
Disparidades nos Níveis de Saúde , Lúpus Eritematoso Sistêmico , Complicações na Gravidez , Grupos Raciais , Feminino , Humanos , Gravidez , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Fatores de Risco , Estados Unidos/epidemiologia , Brancos , Negro ou Afro-AmericanoRESUMO
OBJECTIVE: Sleep quality and duration are important for biological restoration and promotion of psychological well-being. Optimism may facilitate or result from sufficient sleep, but questions remain as to directionality. The present study tested how optimism is associated with levels of and variability in sleep quantity and quality in a longitudinal burst design. METHODS: Midlife and older women ( N = 199) reported their sleep quantity and quality in online diaries for a 7-day period, every 3 months for 2 years. Optimism was measured at baseline and end-of-study. Multilevel models tested the effects of optimism on sleep. Linear regression models tested the effect of sleep on optimism. RESULTS: Baseline optimism was associated with higher sleep quality ( γ = 2.13 [1.16 to 3.11], p < .0001) and lower intraindividual variability (IIV; night-to-night and wave-to-wave) in sleep quantity (night-to-night: γ = -0.07 [-0.13 to -0.005], p = .03; wave-to-wave: b = -0.07 [-0.12 to -0.02], p = .003). In turn, higher average sleep quality (but not quantity) was associated with higher optimism at end-of-study ( b = 0.02 [0.007 to 0.03], p = .002). Variability in sleep was unrelated to optimism. CONCLUSIONS: Optimism may play an important role in maintaining sleep quality and consistency in sleep quantity, perhaps by buffering stress. Similarly, sleep quality may play an important role in maintaining optimism. The cycle whereby optimism and sleep enhance one another could improve physical health and psychological well-being among aging adults.
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Envelhecimento , Otimismo , Qualidade do Sono , Humanos , Feminino , Pessoa de Meia-Idade , Otimismo/psicologia , Idoso , Envelhecimento/fisiologia , Estudos Longitudinais , Sono/fisiologiaRESUMO
Inflammation involves a delicate balance between pathogen clearance and limiting host tissue damage, and perturbations in this equilibrium promote disease. Patients suffering from autoimmune diseases, such as systemic lupus erythematosus (SLE), have higher levels of serum S100A9 protein and increased risk for infection. S100A9 is highly abundant within neutrophils and modulates antimicrobial activity in response to bacterial pathogens. We reasoned that increased serum S100A9 in SLE patients reflects accumulation of S100A9 protein in neutrophils and may indicate altered neutrophil function. In this study, we demonstrate elevated S100A9 protein within neutrophils from SLE patients, and MRL/lpr mice associates with lower mitochondrial superoxide, decreased suicidal neutrophil extracellular trap formation, and increased susceptibility to Staphylococcus aureus infection. Furthermore, increasing mitochondrial superoxide production restored the antibacterial activity of MRL/lpr neutrophils in response to S. aureus These results demonstrate that accumulation of intracellular S100A9 associates with impaired mitochondrial homeostasis, thereby rendering SLE neutrophils inherently less bactericidal.
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Calgranulina B/sangue , Armadilhas Extracelulares/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Mitocôndrias/metabolismo , Staphylococcus aureus/imunologia , Animais , Suscetibilidade a Doenças/imunologia , Feminino , Homeostase/fisiologia , Humanos , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/crescimento & desenvolvimento , Superóxidos/metabolismoRESUMO
OBJECTIVES: Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes. METHODS: We used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial. RESULTS: Comparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-ß, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54. CONCLUSIONS: Our results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Escleroderma Sistêmico , Humanos , Autoanticorpos , Escleroderma Sistêmico/patologia , Transplante de Células-Tronco Hematopoéticas/métodos , Ciclofosfamida/uso terapêutico , Transplante AutólogoRESUMO
OBJECTIVES: Myeloablative autologous haematopoietic stem cell transplant (HSCT) was recently demonstrated to provide significant benefit over cyclophosphamide (CYC) in the treatment of diffuse cutaneous systemic sclerosis (dcSSc) in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. As dysregulation of the B cell compartment has previously been described in dcSSc, we sought to gain insight into the effects of myeloablative autologous HSCT as compared with CYC. METHODS: We sequenced the peripheral blood immunoglobulin heavy chain (IGH) repertoires in patients with dcSSc enrolled in the SCOT trial. RESULTS: Myeloablative autologous HSCT was associated with a sustained increase in IgM isotype antibodies bearing a low mutation rate. Clonal expression was reduced in IGH repertoires following myeloablative autologous HSCT. Additionally, we identified a underusage of immunoglobulin heavy chain V gene 5-51 in patients with dcSSc, and usage normalised following myeloablative autologous HSCT but not CYC treatment. CONCLUSIONS: Together, these findings suggest that myeloablative autologous HSCT resets the IGH repertoire to a more naïve state characterised by IgM-expressing B cells, providing a possible mechanism for the elimination of pathogenic B cells that may contribute to the benefit of HSCT over CYC in the treatment of dcSSc.
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Transplante de Células-Tronco Hematopoéticas , Esclerodermia Difusa , Escleroderma Sistêmico , Humanos , Escleroderma Sistêmico/cirurgia , Escleroderma Sistêmico/patologia , Ciclofosfamida/uso terapêutico , Esclerodermia Difusa/terapia , Transplante Autólogo , Cadeias Pesadas de Imunoglobulinas/genéticaRESUMO
Autoreactive B cell subsets have been described in a variety of settings, using multiple classification schemes and cell surface markers also found on healthy cells. CD19+ CD21lo B cells have been identified as an autoreactive-prone subset of B cells, although the downregulation of CD21 has been observed on a variety of B cell subsets in health and disease. This variation has led to confusion regarding the meaning and applicability of the loss or reduction of CD21 in peripheral B cells. To better understand the relationships between commonly used B cell markers and their associated characteristics, we analyzed human B cells from healthy participants using multiparameter flow cytometry and the visualization algorithm, tSNE. This approach revealed significant phenotypic overlap amongst five previously described autoimmune-prone B cell subsets, including CD19+ CD10- CD27- CD21lo B cells. Interestingly, 12 different subpopulations of CD19+ CD21lo B cells were identified, some of which mapped to previously described autoreactive populations, while others were consistent with healthy B cells. This suggests that CD21 is downregulated in a variety of circumstances involving B cell activation, all of which are present in low numbers even in healthy individuals. These findings describe the utility of unbiased multiparameter analysis using a relatively limited panel of flow cytometry markers to analyze autoreactive-prone and normal activated B cells.
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Subpopulações de Linfócitos B , Linfócitos B , Humanos , Algoritmos , Citometria de Fluxo , Voluntários Saudáveis , Receptores de Complemento 3dRESUMO
OBJECTIVE: Shorter sleep duration and more sleep disturbances, in addition to greater night-to-night fluctuations in sleep (intraindividual variability; IIV), have been associated with elevated inflammation. However, these associations were only at the between-person level. The current study examined the within-person relationship between mean levels and IIV of sleep duration and sleep disturbances and C-reactive protein (CRP) in healthy, aging women. METHODS: Participants ( N = 179) from a longitudinal study of activity and well-being in middle-aged and older women (mean age = 62 years; range = 50-75 years) completed a 7-day daily diary, every 3 months, for 2 years (up to nine bursts). Sleep was assessed each day asking participants how many hours of sleep they got the night before and with the four-item PROMIS Sleep Disturbance Short Form. Finger-stick dried blood spot samples were collected after each 7-day daily diary. RESULTS: In bursts when women experienced greater than average variability in sleep duration, they had higher CRP ( γ = 0.06, p = .004). Within-person changes in mean sleep duration were not associated with CRP. In addition, neither mean sleep disturbances nor sleep disturbance IIV were associated with CRP. CONCLUSIONS: This study is the first to show that within-person changes in variable sleep duration are related to changes in inflammation. Findings from the current study suggest that greater variability in sleep duration is related to higher CRP, which may increase risk for early morbidity and mortality. Future studies should investigate inflammation as a pathway linking sleep variability and health.
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Transtornos do Sono-Vigília , Sono , Pessoa de Meia-Idade , Humanos , Feminino , Idoso , Estudos Longitudinais , Transtornos do Sono-Vigília/epidemiologia , Inflamação , Proteína C-Reativa/metabolismoRESUMO
Fibromyalgia (FM) is a chronic pain disorder characterized by chronic widespread musculoskeletal pain (CWP), resting pain, movement-evoked pain (MEP), and other somatic symptoms that interfere with daily functioning and quality of life. In clinical studies, this symptomology is assessed, while preclinical models of CWP are limited to nociceptive assays. The aim of the study was to investigate the human-to-model translatability of clinical behavioral assessments for spontaneous (or resting) pain and MEP in a preclinical model of CWP. For preclinical measures, the acidic saline model of FM was used to induce widespread muscle pain in adult female mice. Two intramuscular injections of acidic or neutral pH saline were administered following baseline measures, 5 days apart. An array of adapted evoked and spontaneous pain measures and functional assays were assessed for 3 weeks. A novel paradigm for MEP assessment showed increased spontaneous pain following activity. For clinical measures, resting and movement-evoked pain and function were assessed in adult women with FM. Moreover, we assessed correlations between the preclinical model of CWP and in women with fibromyalgia to examine whether similar relationships between pain assays that comprise resting and MEP existed in both settings. For both preclinical and clinical outcomes, MEP was significantly associated with mechanical pain sensitivity. Preclinically, it is imperative to expand how the field assesses spontaneous pain and MEP when studying multi-symptom disorders like FM. Targeted pain assessments to match those performed clinically is an important aspect of improving preclinical to clinical translatability of animal models.
Assuntos
Dor Crônica , Fibromialgia , Dor Musculoesquelética , Adulto , Animais , Feminino , Fibromialgia/diagnóstico , Humanos , Camundongos , Medição da Dor , Qualidade de VidaRESUMO
Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological intervention used in the treatment of acute and chronic pain conditions. The first clinical studies on TENS were published over 50 years ago, when effective parameters of stimulation were unclear and clinical trial design was in its infancy. Over the last two decades, a better understanding of the mechanisms underlying TENS efficacy has led to the development of an adequate dose and has improved outcome measure utilization. The continued uncertainty about the clinical efficacy of TENS to alleviate pain, despite years of research, is related to the quality of the clinical trials included in systematic reviews. This summary of the evidence includes only trials with pain as the primary outcome. The outcomes will be rated as positive (+), negative (-), undecided (U), or equivalent to other effective interventions (=). In comparison with our 2014 review, there appears to be improvement in adverse events and parameter reporting. Importantly, stimulation intensity has been documented as critical to therapeutic success. Examinations of the outcomes beyond resting pain, analgesic tolerance, and identification of TENS responders remain less studied areas of research. This literature review supports the conclusion that TENS may have efficacy for a variety of acute and chronic pain conditions, although the magnitude of the effect remains uncertain due to the low quality of existing literature. In order to provide information to individuals with pain and to clinicians treating those with pain, we suggest that resources for research should target larger, high-quality clinical trials including an adequate TENS dose and adequate timing of the outcome and should monitor risks of bias. Systematic reviews and meta-analyses should focus only on areas with sufficiently strong clinical trials that will result in adequate sample size.
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Dor Crônica , Estimulação Elétrica Nervosa Transcutânea , Humanos , Estimulação Elétrica Nervosa Transcutânea/efeitos adversos , Dor Crônica/terapia , Revisões Sistemáticas como Assunto , Manejo da Dor , Analgésicos , Doença CrônicaRESUMO
BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).
Assuntos
Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Escleroderma Sistêmico/terapia , Adolescente , Adulto , Idoso , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunossupressores/efeitos adversos , Infecções/etiologia , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/mortalidade , Condicionamento Pré-Transplante , Transplante Autólogo , Adulto JovemRESUMO
BACKGROUND: Disturbed sleep is prevalent in older adulthood and particularly among women. Greater psychological well-being (PWB) is associated with better sleep, but intraindividual variability in PWB has not been examined. PURPOSE: The current study examined whether mean levels and variability in PWB were associated with sleep disturbances in midlife and older women. METHODS: Participants (N = 189) completed up to seven daily diaries and an end of the week assessment every 3 months for nine waves. Participants answered questions about their nightly sleep disturbances and reported their PWB using Ryff's six dimensions of PWB. RESULTS: Regression models indicated that greater variability in one aspect of PWB, positive relations with others, was related to greater sleep disturbance even after adjusting for mean levels of well-being. Greater variability in environmental mastery, purpose in life, and self-acceptance were also associated with sleep disturbance, but these associations were no longer significant after adjusting for mean levels of well-being. CONCLUSIONS: Results suggest that fluctuations in positive relations with others are related to sleep in adult women above and beyond mean levels of well-being. Results highlight the importance of considering variability in addition to mean levels of PWB.
Assuntos
Envelhecimento/psicologia , Saúde Mental , Sono , Mulheres/psicologia , Idoso , Diários como Assunto , Feminino , Humanos , Relações Interpessoais , Estudos Longitudinais , Pessoa de Meia-Idade , Testes PsicológicosRESUMO
OBJECTIVE: To examine the impact of educational materials for chronic overlapping pain conditions (COPCs), the feasibility of delivering materials online, and to explore its impact on self-reported self-management applications at 3-month follow-up. DESIGN: Prospective cohort study. SETTING: Online. SUBJECTS: Individuals from a university-wide active research repository with ≥1 coded diagnostic COPC by ICD-9/10 in the medical record. METHODS: We determined the number of COPCs per participant as indicated by diagnostic codes in the medical record. Consenting participants completed self-report questionnaires and read educational materials. We assessed content awareness and knowledge pre- and post-exposure to education. Comprehension was assessed via embedded questions in reading materials in real time. Participants then completed assessments regarding concept retention, self-management engagement, and pain-related symptoms at 3-months. RESULTS: N = 216 individuals enrolled, with 181 (84%) completing both timepoints. Results indicated that participants understood materials. Knowledge and understanding of COPCs increased significantly after education and was retained at 3-months. Patient characteristics suggested the number of diagnosed COPCs was inversely related to age. Symptoms or self-management application did not change significantly over the 3-month period. CONCLUSIONS: The educational materials facilitated teaching of key pain concepts in self-management programs, which translated easily into an electronic format. Education alone may not elicit self-management engagement or symptom reduction in this population; however, conclusions are limited by the study's uncontrolled design. Education is likely an important and meaningful first step in comprehensive COPC self-management.
Assuntos
Dor Crônica , Eletrônica , Humanos , Estudos ProspectivosRESUMO
OBJECTIVE: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT. METHODS: We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs). RESULTS: Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways. CONCLUSIONS: Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT.
Assuntos
Perfilação da Expressão Gênica/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Aprendizado de Máquina , Esclerodermia Difusa/classificação , Esclerodermia Difusa/terapia , Adulto , Ciclofosfamida/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerodermia Difusa/patologia , Transcriptoma , Resultado do TratamentoRESUMO
BACKGROUND: Pain interferes with people's daily lives and often limits the extent to which they can pursue goals and engage in activities that promote well-being. However, people vary in how much interference they experience at a given level of pain. PURPOSE: The present study tested how optimism affects and is affected by pain interference and goal-directed activity among older women. METHODS: Every 3 months for 2 years, community-dwelling middle- and older-age women (N = 199) completed online daily diaries at home for a 7 day period, in which they reported their daily pain, pain interference, and goal-directed activity. Optimism was measured at the start and end of the study. Multilevel models tested the between- and within-person relationships among pain, optimism, and pain interference or goal-directed activity. Linear regression predicted change in optimism over 2 years from pain interference and goal-directed activity. RESULTS: Pain best predicted pain interference and optimism best predicted goal-directed activity. There were subtle interactions between optimism and pain-predicting interference and goal-directed activity. Accumulated goal-directed activity and pain interference across the study predicted longitudinal changes in optimism, with higher activity and lower pain interference predicting increased optimism over 2 years. CONCLUSIONS: Optimism may play a protective role in disruptions caused by pain on a day-to-day basis, leading to increased goal-directed activity and possibly decreased pain interference. In turn, less interference and more goal-directed activity feed forward into increased optimism, resulting in a virtuous cycle that enhances optimism and well-being among older women.
Assuntos
Atividades Cotidianas/psicologia , Envelhecimento/psicologia , Objetivos , Otimismo/psicologia , Dor/psicologia , Psicometria/normas , Qualidade de Vida/psicologia , Idoso , Feminino , Humanos , Vida Independente , Estudos Longitudinais , Pessoa de Meia-Idade , Psicometria/instrumentação , Reprodutibilidade dos TestesRESUMO
The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE2, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE2 levels and is highly expressed at sites of inflammation. PGE2 is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4+ regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1-/- CD4+ cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE2 by cocultured APCs synergized with that of Ag-experienced CD4+ T cells, with mPGES1 competence in the APC compartment enhancing CD4+ IL-17A and IFN-γ responses. However, in contrast with CD4+ cells that were Ag primed in vivo, exogenous PGE2 inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE2 production that impacts effector T cell IL-17A and IFN-γ responses.
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Comunicação Autócrina , Dinoprostona/metabolismo , Comunicação Parácrina , Prostaglandina-E Sintases/genética , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Epitopos de Linfócito T/imunologia , Regulação da Expressão Gênica , Imunização , Imunomodulação , Ativação Linfocitária/imunologia , Camundongos , Fenótipo , Prostaglandina-E Sintases/metabolismo , Receptores de Prostaglandina E Subtipo EP2/genética , Receptores de Prostaglandina E Subtipo EP4/genéticaRESUMO
OBJECTIVE: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. METHODS: Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. RESULTS: At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. CONCLUSION: HSCT contrary to conventional treatment leads to a significant 'correction' in disease-related molecular signatures.
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Interferons/sangue , Neutrófilos/metabolismo , Escleroderma Sistêmico/genética , Transcriptoma , Condicionamento Pré-Transplante/métodos , Adulto , Ciclofosfamida/uso terapêutico , Regulação para Baixo , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multinível , Agonistas Mieloablativos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/terapia , Transplante Autólogo , Resultado do Tratamento , Regulação para CimaRESUMO
Prostaglandins (PG) are pleiotropic bioactive lipids involved in the control of many physiological processes, including key roles in regulating inflammation. This links PG to the modulation of the quality and magnitude of immune responses. T cells, as a core part of the immune system, respond readily to inflammatory cues from their environment, and express a diverse array of PG receptors that contribute to their function and phenotype. Here we put in context our knowledge about how PG affect T cell biology, and review advances that bring light into how specific T cell functions that have been newly discovered are modulated through PG. We will also comment on drugs that target PG metabolism and sensing, their effect on T cell function during disease, and we will finally discuss how we can design new approaches that modulate PG in order to maximize desired therapeutic T cell effects.
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Prostaglandinas/imunologia , Linfócitos T/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Diferenciação Celular/efeitos dos fármacos , Descoberta de Drogas , Humanos , Imunidade/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Prostaglandinas/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
PURPOSE: The relationship between exposure to abuse and interstitial cystitis/bladder pain syndrome (IC/BPS) is well-documented. However, studies have yet to examine posttraumatic stress disorder (PTSD), which develops following exposure to trauma and worsens health outcomes in chronic pain. We aimed to assess the prevalence and impact of PTSD in patients with IC/BPS, including their relation to genitourinary symptom presentation and widespread pain phenotype. MATERIALS AND METHODS: We recruited 202 participants with chronic pain from an academic medical center and classified 64 individuals as IC/BPS based on validated epidemiological criteria. Participants completed self-reported questionnaires assessing trauma exposure, PTSD symptoms, emotional distress, pain, and urinary symptoms. Wilcoxon rank-sum tests assessed study aims comparing IC/BPS to other chronic pain. RESULTS: Although elevated, IC/BPS trauma exposure rates were equivalent to that of other chronic pain conditions in the sample. Despite this equivalence, in comparison, IC/BPS patients had significantly higher rates of PTSD symptoms, with 42% meeting provisional diagnostic criteria for PTSD. Among IC/BPS, those meeting provisional criteria for PTSD had significantly higher incidence of lifetime sexual abuse, childhood trauma, and presentations consistent with the widespread pain phenotype. In IC/BPS, there was no association between PTSD and genitourinary symptoms, but provisional PTSD was associated with more pain, emotional distress, and poorer quality of life. CONCLUSIONS: We recommend that patients with IC/BPS and widespread pain have ongoing screening and monitoring of PTSD. We recommend using trauma-informed care practices with these patients to increase trust and safety, which could improve treatment compliance and follow-up.
Assuntos
Dor Crônica/epidemiologia , Cistite Intersticial/epidemiologia , Qualidade de Vida/psicologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Adulto , Dor Crônica/psicologia , Comorbidade , Cistite Intersticial/psicologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Transtornos de Estresse Pós-Traumáticos/psicologia , Inquéritos e QuestionáriosRESUMO
Systemic sclerosis is a progressive inflammatory disease that is frequently fatal and has limited treatment options. High-dose chemotherapy with autologous hematopoietic cell transplantation (AHCT) has been evaluated as treatment for this disease in observational studies, multicenter randomized controlled clinical trials, and meta-analyses. On behalf of the American Society for Blood and Marrow Transplantation (ASBMT), a panel of experts in transplantation and rheumatology was convened to review available evidence and make a recommendation on AHCT as an indication for systemic sclerosis. Three randomized trials have compared the efficacy of AHCT with cyclophosphamide only, and all demonstrated benefit for the AHCT arm for their primary endpoint (improvement in the American Scleroderma Stem Cell versus Immune Suppression Trial, event-free survival in Autologous Stem Cell Transplantation International Scleroderma trial, and change in global rank composite score in Scleroderma: Cyclophosphamide or Transplantation trial). AHCT recipients also had better overall survival and a lower rate of disease progression. These findings have been confirmed in subsequent meta-analyses. Based on this high-quality evidence, the ASBMT recommends systemic sclerosis should be considered as a "standard of care" indication for AHCT. Close collaboration between rheumatologists and transplant clinicians is critical for optimizing patient selection and patient outcomes. Transplant centers in the United States are strongly encouraged to report patient and outcomes data to the Center for International Blood and Marrow Transplant Research on their patients receiving AHCT for this indication.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Escleroderma Sistêmico/terapia , Autoenxertos , Transplante de Medula Óssea , Ciclofosfamida/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Escleroderma Sistêmico/mortalidade , Escleroderma Sistêmico/patologia , Sociedades Médicas , Estados UnidosRESUMO
AIMS: Psychosocial factors amplify symptoms of Interstitial Cystitis (IC/BPS). While psychosocial self-management is efficacious in other pain conditions, its impact on an IC/BPS population has rarely been studied. The objective of this review is to learn the prevalence and impact of psychosocial factors on IC/BPS, assess baseline psychosocial characteristics, and offer recommendations for assessment and treatment. METHOD: Following PRISMA guidelines, primary information sources were PubMed including MEDLINE, Embase, CINAHL, and GoogleScholar. Inclusion criteria included: (i) a clearly defined cohort with IC/BPS or with Chronic Pelvic Pain Syndrome provided the IC/BPS cohort was delineated with quantitative results from the main cohort; (ii) all genders and regions; (iii) studies written in English from 1995 to April 14, 2017; (iv) quantitative report of psychosocial factors as outcome measures or at minimum as baseline characteristics. RESULTS: Thirty-four of an initial 642 articles were reviewed. Quantitative analyses demonstrate the magnitude of psychosocial difficulties in IC/BPS, which are worse than average on all measures, and fall into areas of clinical concern for 7 out of 10 measures. Meta-analyses shows mean Mental Component Score of the Short-Form 12 Health Survey (MCS) of 40.80 (SD 6.25, N = 2912), where <36 is consistent with severe psychological impairment. Averaged across studies, the population scored in the range seen in clinical depression (CES-D 19.89, SD 13.12, N = 564) and generalized anxiety disorder (HADS-A 8.15, SD 4.85, N = 465). CONCLUSION: The psychological impact of IC/BPS is pervasive and severe. Existing evidence of treatment is lacking and suggests self-management intervention may be helpful.