Developments in the scientific understanding of lupus

Systemic lupus erythematosus is a systemic autoimmune disease characterized by the production of antinuclear antibodies (ANAs). Recent research into human and murine lupus suggests that disease susceptibility results from genetic polymorphisms regulating immune responses as well as impairing the clearance of apoptotic cells. Because the products of dead cells, including nucleic acids, have immunologic activity, this situation can promote antigen-driven ANA responses. Furthermore, immune complexes of ANAs can drive the production of proinflammatory cytokines, inducing the 'interferon signature', and intensifying disease. Together, these findings point to new genetic and immunologic markers of disease as well as targets for new therapies

Development of a novel renal activity index of lupus nephritis in children & young adults

BACKGROUND: Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histological LN activity. METHODS: We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n=47) at the time of kidney biopsy. Histological LN activity was measured by the NIH Activity Index (NIH-AI) and the Tubulointerstitial Activity Index (TIAI). High LN-activity status (vs. moderate/low) was defined as NIH-AI scores \u3e 10 (vs.5 (vs.92% accuracy and LN-activityTIAI status with \u3e80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71 and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses. CONCLUSION: The RAIL is a robust and highly accurate noninvasive measure of LN-activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation. This article is protected by copyright. All rights reserved

Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis

BACKGROUND: To reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy.METHODS: Forty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months.RESULTS: The majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF.CONCLUSIONS: Overall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research

The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation

Cell death is critical to normal homeostasis, although this process, when increased aberrantly, can lead to the production of pro-inflammatory mediators promoting autoimmunity. Two novel intercellular mediators of inflammation generated during cell death are high mobility group box 1 (HMGB1) protein and microparticles (MPs). HMGB1 is a nuclear protein that functions in transcription when inside the nucleus but takes on pro-inflammatory properties when released during cell death. Microparticles are small, membrane-bound structures that extrude from cells when they die and contain cell surface proteins and nuclear material from their parent cells. MPs circulate widely throughout the vasculature and mediate long-distance communication between cells. Both MPs and HMGB1 have been implicated in the pathogenesis of a broad spectrum of inflammatory diseases, including the prototypic autoimmune conditions systemic lupus erythematosus and rheumatoid arthritis. Given their range of activity and association with active disease, both structures may prove to be targets for effective therapy in these and other disorders

Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults

OBJECTIVE: Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity. METHODS: We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH-AI) and the tubulointerstitial activity index (TIAI). High LN-activity status (versus moderate/low) was defined as NIH-AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN-activity status for both NIH-AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN-activity status was determined. RESULTS: The differential excretion of 6 UBMs (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN-activity (NIH-AI) status with >92% accuracy and LN-activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses. CONCLUSION: The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation

American College of Rheumatology Provisional Criteria for Global Flares in Childhood-Onset Systemic Lupus Erythematosus

Objective: To validate the preliminary criteria of global flare for childhood-onset SLE (cSLE). Methods: Pediatricians experienced in cSLE care (n = 268) rated unique patient profiles; results of standard cSLE laboratory testing and information about the cSLE flare descriptors were presented as follows: global assessment of patient well-being, physician global assessment of disease activity (MD-global), Disease Activity Index score, protein/creatinine ratio (PCR), and erythrocyte sedimentation rate (ESR). Using rater interpretation of the course of cSLE (baseline versus followup as the gold standard), performance (sensitivity, specificity, area under the receiver operating characteristic curve [AUC]) of the preliminary flare criteria was tested. An international consensus conference was held to rank the preliminary flare criteria as per the American College of Rheumatology recommendations and delineate threshold scores for minor, moderate, and major flares. Results: The accuracy of the 2 highest-ranked candidate criteria that consider absolute changes ( 06) of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) or British Isles Lupus Assessment Group (BILAG) (numeric scoring: A = 12, B = 8, C = 1, and D/E = 0), MD-global, PCR, and ESR were confirmed (both AUC >0.93). For the SLEDAI-based criteria (0.5 7 06SLEDAI + 0.45 7 06PCR + 0.5 7 06MD-global + 0.02 7 06ESR) flare scores 656.4/3.0/0.6 constituted major/moderate/minor flares, respectively. For the BILAG-based algorithm (0.4 7 06BILAG + 0.65 7 06PCR + 0.5 7 06MD-global + 0.02 7 06ESR) flare scores 657.4/3.7/2.2 delineated major/moderator/minor flares, respectively. These threshold values (SLEDAI, BILAG) were all >82% sensitive and specific for capturing flare severity. Conclusion: Provisional criteria for global flares in cSLE are available to identify patients who experienced a flare. These criteria also allow for discrimination of the severity of cSLE exacerbations

Monitoreo del progreso del alumno en la identificación de riesgo en la lectura

Este estudo tem por nalidade analisar o uso da monitorização com base no currículo como sistema escolar de identi cação de alunos em risco na leitura, no contexto de um modelo educativo baseado no grau de resposta à intervenção. Realizou-se uma investigação quantitativa em que participaram todos os alunos do 3o ano (82 alunos) de um agrupamento de escolas do norte de Portugal. O tratamento de dados foi feito com recurso à estatística descritiva e inferencial. Destacam-se, entre outras conclusões, a existência de dez alunos em risco na leitura durante todo o ano letivo e o facto de, no nal do 3o ano de escolaridade, a média de resultados dos alunos que nunca estiveram em risco ser superior ao dobro da média de resultados dos alunos que estiveram em risco todo o ano.This study aims to analyze the use of curriculum-based monitoring as a school system to identify students at risk in reading, in the context of an educational model based on the degree of response to intervention. A quantitative investigation was conducted with all third grade students (82 students) from a group of schools in the north of Portugal. Data processing was done using descriptive and inferential statistics. Among the conclusions, the following stand out: the existence of ten students at risk in reading throughout the school year and the fact that, at the end of the third year of schooling, the mean results of students who were never at risk was more than double the mean results of students who were at risk for the entire year.Cette étude a pour but d’analyser l’usage du contôle ayant pour base le coursus comme système scolaire d’identification des élèves présentant des risques dans la lecture, dans le contexte d’un modèle éducatif fondé sur le degrée de réponse à l’intervention. On a fait une investigation quantitative à laquelle ont participé tous les élèves de CM1 (82 élèves) d’un groupement d’écoles du nord du Portugal. Le traitement des données a été fait à l’aide de la statistique descriptive et inférentielle. On souligne, entre autres conclusions, l’existence de dix élèves en risque dans la lecture pendant toute l’année scolaire et le fait qu’à la fin de la troisièmme année de scolarité, la moyenne des résultats des élèves n’ayant jamais été en risque soit supérieur au double de la moyenne des résultats des élèves qui ont été en risque toute l’année.Este estudio tiene la finalidad de analizar el uso del monitoreo del currículo como sistema escolar de identificación de alumnos en riesgo en la lectura, en el marco de un modelo educativo basado en el grado de respuesta a la intervención. Se llevó a cabo una investigación cuantitativa en la que participaron todos los alumnos del 3er año (82 alumnos) de un agrupamiento de escuelas del norte de Portugal. El tratamiento de datos se efectuó por medio de la estadística descriptiva e de inferencias. Se destacan, entre otras conclusiones, la existencia de diez alumnos en riesgo en la lectura durante todo el año lectivo y el hecho de que, al final del 3er año de escolaridad, el promedio de resultados de los alumnos que nunca estuvieron en riesgo era superior al doble del promedio de resultados de los alumnos que estuvieron en riesgo todo el año.(undefined)info:eu-repo/semantics/publishedVersio

Circulating microparticles: square the circle

Background: The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results: MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions: Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes