Co-Expression Profile of TNF Membrane-Bound Receptors Type 1 and 2 in Rheumatoid Arthritis on Immunocompetent Cells Subsets.

INTRODUCTION: Tumor necrosis factor (TNFα) is an important proinflammatory cytokine in rheumatoid arthritis (RA) immune processes. However, TNFα activity and functions may be regulated by soluble receptors, which act as decoys, and by number, density, and co-expression of its membrane-bound receptors type 1 and 2 (TNFR1 and TNFR2). The aim of this study was to reveal associations between TNFR1/2 co-expression profile parameters and RA disease activity indicators. METHODS: PBMC were analyzed from 46 healthy donors and 64 patients with RA using flow cytometry. Patients were divided according to the disease activity score (DAS) 28 index into groups with high (n = 22, 34.4%), moderate (n = 30, 46.9%), and low (n = 12, 18.8%) disease activity. Co-expression of TNFR1 and TNFR2 was studied by evaluating the percentage of cells, with different receptors, and by counting the number of receptors of each type per cell, using QuantiBritePE beads. Associations between disease severity and activity indicators and parameters of TNFα receptor expression in subpopulations of immune cells were studied. RESULTS: T cell subsets from RA patients were characterized by co-expression of TNFR1 and TNFR2, and were found to differ significantly compared with healthy donors. Memory cells both among T helper cells and cytotoxic T cells demonstrated the most significant differences in TNFR-expression profile. Multivariable logistic regression revealed model to identified RA patients from healthy individual based on the TNFR1/2 co-expression parameters. CONCLUSION: The profile of TNFR1\2 co-expression differs in RA comparing with health. Proportion of TNFR1+TNFR2- cells increased significantly among memory T helper cells and activated cytotoxic T cells, and decreased significantly among naïve cytotoxic T cells and T regulatory cells as compared with health. The parameters of TNFR1\2 co-expression in RA are associated with clinical and laboratory indicators of disease activity.

Comparative analysis of the etanercept efficacy in children with juvenile idiopathic arthritis under the age of 4 years and children of older age groups using the propensity score matching method.

Objective: The aim of this study was to analyze the efficacy and safety of etanercept (ETA) in children with juvenile idiopathic arthritis (JIA) under the age of 4 years and to compare the data with those for older age groups. Methods: Three groups comprising 34 patients each (total of 102 patients) were selected using the propensity score matching (PSM) method. The study group (patients under the age of 4 years; the Junior group (JNR)) was compared with patients of the older age groups, adjusted for criteria such as gender, JIA category, JIA severity, and either age at disease onset (the Reference by Age of disease Onset (RAO) group) or disease duration (the Reference by Disease Duration (RDD) group). Results: All three groups showed a good response to ETA therapy. During the follow-up period, only 4 (3.9%) patients failed to reach American College of Rheumatology (ACR) Pediatric criteria improvement at ACR50 level. In the JNR group, 82.4% of patients achieved ACR90 within a median time of 3 months (IQR, 3-6 months), which was a better result compared to the other two groups: 61.8% (RAO group) and 58.8% (RDD group) of patients achieved ACR90 within 6 (Interquartile Range (IQR), 3-9) months (p = .028). Three (9%) patients in the JNR group and none of the RDD and RAO groups discontinued treatment because of clinical remission (p = .045). Conclusion: An analysis of the ETA efficacy in different age groups comparable in terms of the diagnosis and disease severity demonstrated a higher efficacy of earlier ETA therapy in children of the same age at disease onset. In children at the early stage of arthritis (≤ 2.5 years long), ETA was more efficient in those with an earlier disease onset.

Expression of TNFα Receptors on Immunocompetent Cells Is Increased in Atopic Dermatitis.

BACKGROUND: Expression levels of cytokine and growth factor receptors have been found to be important in the regulation of their action. Tumor necrosis factor-α (TNFα) is actively involved in inflammation processes in atopic dermatitis (AD), but the role of TNFα membrane receptors (TNFR) and their regulatory function in AD remains unclear. AIM: We aimed to determine the associations of parameters of TNFRα expression on immunocompetent cells with disease severity before and after therapy in AD patients. METHODS: TNFRα expression on T cells, B cells, and monocytes was evaluated by flow cytometry. To determine receptor numbers on the cells, Quantibrite PE beads were used. The content of soluble mediators was evaluated by ELISA. To reveal linear relationships between the index scoring AD (SCORAD) and the studied parameters, multiple linear regression model building was used. RESULTS: TNFR1 and TNFR2 expression in lymphocyte and monocyte populations of AD patients was higher than in healthy individuals (HI). At the same time an increased percentage of positive cells was not associated with high receptor density, and vice versa. Serum content of TNFα, both soluble receptors, the number of TNFR2/T cells, and the percentage of TNFR2+ monocytes were found to be strongly associated with the SCORAD index. CONCLUSION: AD patients had increased TNFR expression on immune cells. Changes in the parameters of TNFRα expression compared to HI were associated with the disease severity index SCORAD.

Redistribution of TNF Receptor 1 and 2 Expression on Immune Cells in Patients with Bronchial Asthma.

BACKGROUND: The co-expression patterns of type 1 and 2 tumor necrosis factor (TNF)-α membrane receptors (TNFR1/TNFR2) are associated with the presence, stage, and activity of allergic diseases. The aim of this study was to assess the expression levels and dynamics of TNFRs on immune cells and to assess associations between their expression and severity of bronchial asthma (BA). METHODS: Patients with severe (n = 8), moderate (n = 10), and mild (n = 4) BA were enrolled. As a comparison group, data from 46 healthy volunteers (HV) were accessed. Co-expression of TNFR1/2 was evaluated as a percentage of cells and the number of receptors of each type per cell. Multivariate logistic regression analysis was used to identify diagnostic biomarkers of BA. RESULTS: More than 90% of the monocytes in patients with mild BA were TNFR1+TNFR2+ but had significantly lower TNFR1 expression density compared with HV (7.82- to 14.08-fold, depending on disease severity). Lower percentages of the TNFR+ B-lymphocytes were observed in combination with significantly lower receptors density in BA compared with HV (2.59- to 11.64-fold for TNFR1 and 1.72- to 3.4-fold for TNFR2, depending on disease severity). The final multivariate model for predicting the presence of BA included the percentage of double-positive CD5+ B-lymphocytes and average number of TNFR1 molecules expressed on cytotoxic naive T-lymphocytes and T-helper cells (R2 = 0.87). CONCLUSIONS: The co-expression patterns of TNFRs on immune cells in BA differed significantly compared with HV. The expression differences were associated with disease severity. TNFR1 expression changes were key parameters that discriminated patients with BA from those with HV.

Dynamics of concomitant therapy in children with juvenile idiopathic arthritis treated with etanercept and methotrexate.

BACKGROUND: Both the steroid- and NSAID-sparing effects of biologics in juvenile idiopathic arthritis (JIA) treatment are key aspects of the dynamics of patient's condition. The proper selection of biologics enables maximum treatment effectiveness and reduction of the dosage of concomitant therapy. Our aim was to study the dynamics of concomitant therapy during etanercept (ETA) and methotrexate (MTX) treatment in patients with JIA. METHODS: This analysis included 215 JIA patients (63.3% females) showing sufficient response to main therapy. One hundred patients received MTX as main therapy, 24 received ETA monotherapy, and 91 received ETA þ MTX combination therapy. The dynamics of concomitant therapy were analyzed after 1 month, every 3 months during the first year, and every 6 months during the long-term follow-up (up to 5 years). RESULTS: At the baseline, 24 (11.2%) patients received concomitant oral glucocorticoids (orGCs) and NSAIDs; the remaining 191 (88.8%) patients were treated with concomitant NSAIDs only. Within 1-year treatment, NSAIDs were discontinued in 162 (75.3%) patients. There were no significant differences in the dynamics of withdrawal of NSAIDs in patients who received and did not receive concomitant MTX. However, the percentage of treatment discontinuation in the MTX group was significantly lower compared to the other two groups (p < 0.001). Oral GCs were discontinued completely in 4 children (16.7%), and the dose of oral GCs was reduced in another 4 patients (16.7%). By the end of the follow-up period, 44 of 115 patients (38.3%) treated with ETA in combination with any concomitant therapy could switch to ETA monotherapy. CONCLUSION: Therapy with ETA makes it possible to reduce the dosage or completely discontinue most concomitant medications (orGCs, NSAIDs, MTX) in a significant percentage of patients. This reduces the risk of development of NSAID- and GC-induced pathological conditions, while the effectiveness of therapy of the underlying condition remains high.

Flow diversion versus parent artery occlusion with bypass in the treatment of complex intracranial aneurysms: Immediate and short-term outcomes of the randomized trial.

OBJECTIVE: We performed prospective randomized comparison of clinical and surgical outcomes of flow diversion versus PVO and bypass in patients with complex anterior circulation aneurysms. PATIENTS AND METHODS: Open, prospective, randomized, parallel group, multicenter study of complex intracranial aneurysms treatment was conducted. Patients with complex intracranial aneurysms of anterior circulation with neck is more than 4 mm wide, dome/neck ratio is equal or less than 2:1, which is suitable for flow diversion and occlusion with bypass were included in the study. A total of 111 potential participants were enrolled since March 2015. Additional propensity score matching was performed with 40 patients in each group selected for analysis. RESULTS: 39 out of 40 patients (97.5%) from matched FD group reached good clinical outcome. In the matched bypass group acceptable outcome was achieved in 32 (80%) out of 40 patients (difference between groups p = 0.029). The morbidity and mortality rates were 15% and 5%, respectively. Difference in the rates of favorable outcomes, compared by χ2 met statistical significance (p = 0.014). The rate of complete aneurysm occlusion at 6 months was 42.5% in the FD group and 95% in surgical group (p < 0.0001). The rate of complete occlusion at 12 months was 65% in the FD group and 97.5% in surgical group. The difference between groups was still significant (p = 0.001). There were no significant differences between groups by occurrence of ischemic (p = 0.108) and hemorrhagic (p = 0.615) complications. CONCLUSION: The study demonstrated superior clinical outcomes for endovascular flow diversion in comparison with bypass surgery in treatment of complex aneurysms. Though, both techniques grant similar percentage of major neurologic complications and comparable cure rate for cranial neuropathy. Nevertheless, flow diversion is associated with significantly lower early obliteration rate, thus possesses patient for risks of prolonged dual antiplatelet regimen and delayed rupture. Hence, it's important to stratify patient by the natural risk of aneurysm rupture prior to treatment selection.

Aspects of the use of propensity score matching methods in neurosurgery / Aspectos do uso dos métodos de pareamento de escore de propensão em neurocirurgia / Aspectos del uso de los métodos de emparejamiento de puntaje de propensión en neurocirugía

ABSTRACT Objective Observational studies and register data provide researchers with ample opportunities to obtain answers to questions that randomized controlled trials cannot answer for organizational or ethical reasons. One of the most common tools for solving this problem is the use of propensity score matching (PSM) methods. The purposes of our study were to compare various models and algorithms for selecting PSM parameters, using retrospective clinical data, and to compare the results obtained using the PSM method with those of prospective studies. Methods The results of two studies (randomized prospective and retrospective) conducted at the Novosibirsk Research Institute of Traumatology and Orthopedics were used for comparative analysis. The trials aimed to study the effectiveness and safety of surgical treatment of degenerative dystrophic lesions in the lumbar spine. We compared the results using the recommended PSM parameters (caliper=0.2 and 0.6) the propensity score is the probability of assignment to one treatment conditional on a subject's measured baseline covariates. Propensity-score matching is increasingly being used to estimate the effects of exposures using observational data. In the most common implementation of propensity-score matching, pairs of treated and untreated subjects are formed whose propensity scores differ by at most a pre-specified amount (the caliper widthand the caliper values often used in real-life studies (0.05, 0.1, 0.25, 0.5, and 0.8) with the those obtained in a similar prospective study. Results After eliminating systematic selection bias, the results of the retrospective and randomized prospective studies were qualitatively comparable. Conclusion The results of this study provide recommendations for the use of PSM: when evaluating efficacy scores in neurosurgical studies (with a sample size < 150 patients), we recommend matching on the logit of the propensity score using calipers of width equal to 0.6 of the standard deviation of the logit of the propensity score. Level of evidence V; Type of study is expert opinion.

RESUMO Objetivos Estudos observacionais e dados de registro fornecem aos pesquisadores amplas oportunidades de obter respostas às perguntas que os estudos clínicos randomizados não podem responder por razões institucionais ou éticas. Uma das ferramentas mais comuns para resolver esse problema é o uso dos métodos de Propensity Score Matching (PSM, pareamento de escore de propensão). O objetivo do nosso estudo foi comparar vários modelos e algoritmos para a seleção de parâmetros de PSM, usando os dados clínicos retrospectivos e comparar os resultados obtidos com esse método com os de estudos prospectivos. Métodos Os resultados de dois estudos (randomizado prospectivo e retrospectivo), realizados no Instituto de Pesquisa de Traumatologia e Ortopedia de Novosibirsk, foram utilizados para análise comparativa. Os estudos visaram estudar a eficácia e a segurança do tratamento cirúrgico de lesões distróficas degenerativas na coluna lombar. Comparamos os resultados usando os parâmetros recomendados pelo PSM, isto é calibração (caliper) de 0,2 e 0,6 e os valores de calibração usados com frequência em estudos da vida real (0,05, 0,1, 0,25, 0,5 e 0,8) com os obtidos em um estudo prospectivo semelhante. Resultados Depois de eliminar o viés sistemático de seleção, os resultados de estudos randomizados prospectivos e retrospectivos foram qualitativamente comparáveis. Conclusões Os resultados deste estudo fornecem recomendações para o uso do PSM: ao avaliar os escores de eficácia em estudos neurocirúrgicos (com tamanho de amostra < 150 pacientes), recomendamos a correspondência do logit do escore de propensão com calibração de largura de 0,6 do desvio padrão do logit do escore de propensão. Nível de evidência V; Opinião do especialista.

RESUMEN Objetivos Los estudios de observación y los datos de registro brindan a los investigadores amplias oportunidades para obtener respuestas a preguntas que los estudios clínicos aleatorizados no pueden responder por razones institucionales o éticas. Una de las herramientas más comunes para resolver este problema es el uso de los métodos de Propensity Score Matching (PSM, emparejamiento de puntaje de propensión). El objetivo de nuestro estudio fue comparar varios modelos y algoritmos para la selección de parámetros de PSM, utilizando los datos clínicos retrospectivos y comparar los resultados obtenidos con ese método con los de estudios prospectivos. Métodos Los resultados de dos estudios (prospectivo aleatorizado y retrospectivo) realizados en el Instituto de Investigación de Traumatología y Ortopedia de Novosibirsk se utilizaron para el análisis comparativo. Los estudios tuvieron como objetivo estudiar la eficacia y seguridad del tratamiento quirúrgico de las lesiones distróficas degenerativas en la columna lumbar. Comparamos los resultados usando los parámetros recomendados por el PSM, esto es, calibración (caliper) de 0,2 y 0,6 y los valores de calibración usados con frecuencia en estudios de la vida real (0,05, 0,1, 0,25, 0,5 y 0,8) con los obtenidos en un estudio prospectivo semejante. Resultados Después de eliminar el sesgo sistemático de selección, los resultados de estudios prospectivos aleatorizados y retrospectivos fueron cualitativamente comparables. Conclusiones Los resultados de este estudio proporcionan recomendaciones para el uso del PSM: al evaluar los puntajes de eficacia en estudios neuroquirúrgicos (con tamaño de muestra <150 pacientes), recomendamos la correspondencia del logit del puntaje de propensión con calibración de ancho de 0.6 de la desviación estándar del logit de puntaje de propensión. Nivel de evidencia V; Opinión del especialista.