Застосування зворотних залежностей у математичних моделях складних об’єктів та систем

Представлено метод побудови апроксимуючих поліноміальних функцій багатьох змінних, який засновано на використанні в поліномах від’ємних степенів та застосуванні до поліномів обмеження на сумарну величину ступеня добутку змінних. Запропоновано використання штрафної функції на кількість членів полінома. Експериментальним шляхом отримано оптимальну величину коефіцієнта запропонованої штрафної функції.Представлен метод построения аппроксимирующих полиномиальных функций многих переменных, основанный на использовании в полиномах отрицательных степеней и применении к полиномам ограничения на суммарную величину степени произведения переменных. Предложено использование штрафной функции на количество членов полинома. Экспериментальным путем получена оптимальная величина коэффициента предложенной штрафной функции.A method of constructing approximating polynomials functions of many variables, based on the use of the negative degrees in polynomials and the application of the limitation on the total value of the product variable to polynoms is presented. The usage of the penalty function for the number of polynomial members is suggested. The optimum value of the proposed penalty functions coefficient is experimentally obtained

Real-world comparison of the effects of etanercept and adalimumab on well-being in non-systemic juvenile idiopathic arthritis: a propensity score matched cohort study

Background: Etanercept (ETN) and adalimumab (ADA) are considered equally efective biologicals in the treat‑ ment of arthritis in juvenile idiopathic arthritis (JIA) but no studies have compared their impact on patient-reported well-being. The objective of this study was to determine whether ETN and ADA have a diferential efect on patientreported well-being in non-systemic JIA using real-world data. Methods: Biological-naive patients without a history of uveitis were selected from the international Pharmachild registry. Patients starting ETN were matched to patients starting ADA based on propensity score and outcomes were collected at time of therapy initiation and 3–12 months afterwards. Primary outcome at follow-up was the improve‑ ment in Juvenile Arthritis Multidimensional Assessment Report (JAMAR) visual analogue scale (VAS) well-being score from baseline. Secondary outcomes at follow-up were decrease in active joint count, adverse events and uveitis events. Outcomes were analyzed using linear and logistic mixed efects models. Results: Out of 158 eligible patients, 45 ETN starters and 45 ADA starters could be propensity score matched result‑ ing in similar VAS well-being scores at baseline. At follow-up, the median improvement in VAS well-being was 2 (inter‑ quartile range (IQR): 0.0 – 4.0) and scores were signifcantly better (P=0.01) for ETN starters (median 0.0, IQR: 0.0 – 1.0) compared to ADA starters (median 1.0, IQR: 0.0 – 3.5). The estimated mean diference in VAS well-being improvement from baseline for ETN versus ADA was 0.89 (95% CI: -0.01 – 1.78; P=0.06). The estimated mean diference in active joint count decrease was -0.36 (95% CI: -1.02 – 0.30; P=0.28) and odds ratio for adverse events was 0.48 (95% CI: 0.16 –1.44; P=0.19). One uveitis event was observed in the ETN group. Conclusions: Both ETN and ADA improve well-being in non-systemic JIA. Our data might indicate a trend towards a slightly stronger efect for ETN, but larger studies are needed to confrm this given the lack of statistical signifcance

Understanding inflammation in juvenile idiopathic arthritis : How immune biomarkers guide clinical strategies in the systemic onset subtype

The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how - through continuous dialogue between bench and bedside - immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL-1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid Related Protein (MRP)-8, MRP-14, S100-A12 and Interleukin-18 are already used daily in clinic as markers for active sJIA. For non-sJIA subtypes, HLA-B27, antinuclear-antibodies, rheumatoid factor, erythrocyte sedimentation rate and C-reactive protein are still used for classification, prognosis or active disease. MRP-8, MRP-14 and S100-A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA

Clinical Juvenile Arthritis Disease Activity Score proves to be a useful tool in treat-to-target therapy in juvenile idiopathic arthritis

OBJECTIVES: To assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX). METHODS: Monocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated. RESULTS: Physicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%-75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti-TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate. CONCLUSIONS: The cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF

The human microbiome and juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The pathogenesis of JIA is thought to be the result of a combination of host genetic and environmental triggers. However, the precise factors that determine one's susceptibility to JIA remain to be unravelled. The microbiome has received increasing attention as a potential contributing factor to the development of a wide array of immune-mediated diseases, including inflammatory bowel disease, type 1 diabetes and rheumatoid arthritis. Also in JIA, there is accumulating evidence that the composition of the microbiome is different from healthy individuals. A growing body of evidence indeed suggests that, among others, the microbiome may influence the development of the immune system, the integrity of the intestinal mucosal barrier, and the differentiation of T cell subsets. In turn, this might lead to dysregulation of the immune system, thereby possibly playing a role in the development of JIA. The potential to manipulate the microbiome, for example by faecal microbial transplantation, might then offer perspectives for future therapeutic interventions. Before we can think of such interventions, we need to first obtain a deeper understanding of the cause and effect relationship between JIA and the microbiome. In this review, we discuss the existing evidence for the involvement of the microbiome in JIA pathogenesis and explore the potential mechanisms through which the microbiome may influence the development of autoimmunity in general and JIA specifically

Increased autophagy contributes to the inflammatory phenotype of juvenile idiopathic arthritis synovial fluid T cells

Objectives: JIA is an autoimmune disease involving disturbed T-cell homeostasis, marked by highly activated effector T cells. Autophagy, a lysosomal degradation pathway, is crucial for maintaining cellular homeostasis by regulating the survival, differentiation and function of a large variety of cells, including T cells. The aim of this study was to examine the rate of autophagy in JIA T cells and to investigate the effect of inhibition of autophagy on the inflammatory phenotype of JIA T cells. Methods: Autophagy-related gene expression was analysed in CD4+ T cells from the SF of JIA patients and healthy controls using RNA sequencing. Autophagy was measured by flow cytometry and western blot. The effect of inhibition of autophagy, using HCQ, on the cellular activation status was analysed using flow cytometry and multiplex immunoassay. Results: Autophagy was increased in T cells derived from the site of inflammation compared with cells from the peripheral blood of patients and healthy controls. This increase in autophagy was not induced by JIA SF, but is more likely to be the result of increased cellular activation. Inhibition of autophagy reduced proliferation, cytokine production and activation marker expression of JIA SF-derived CD4+ T cells. Conclusion: These data indicate that autophagy is increased in JIA SF-derived T cells and that targeting autophagy could be a promising therapeutic strategy to restore the disrupted T-cell homeostasis in JIA