Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.
Цель исследования: сформировать комплекс лабораторных предикторов стеатоза печени при абдоминальном ожирении (АО). Дизайн: скрининговое и сравнительное исследование. Материалы и методы. На этапе скрининга изучены данные профилактических медицинских осмотров лиц с ожирением/избыточным весом (n = 262) и с нормальным весом (n = 100). Для сравнительного исследования сформированы группы здоровых пациентов с АО метаболически «здорового» (n = 23) и нездорового фенотипа (n = 85), больных с АО (n = 31) и здоровых без АО (n = 23). Определяли уровни аланинаминотрансферазы, аспартатаминотрансферазы, γ-глутамилтрансферазы, общего билирубина, глюкозы крови натощак, триглицеридов, общего холестерина, холестерина липопротеинов высокой и низкой плотности, аполипопротеинов A1 и B, высокочувствительного С-реактивного белка, гомоцистеина, инсулина натощак, α2-макроглобулина, гаптоглобина. Стадию поражения печени оценивали по алгоритмам FibroMax и/или SteatoScreen (BioPredictive, Франция) и данным ультразвукового исследования печени. Результаты. Определен интегральный предиктор стеатоза печени с поражением более 32% гепатоцитов с пороговым значением 0,69 (чувствительность-81%, специфичность-88%, р < 0,001). Площадь под ROC-кривой составила 0,910. Заключение. Продемонстрирована прогностичность лабораторных параметров даже среди пациентов с метаболически «здоровым» фенотипом АО. Ключевые слова: абдоминальное ожирение, неалкогольная жировая болезнь печени, превентивная медицина, метаболически «здоровое» ожирение.
Introduction. NAFLD is an urgent health problem, its prevalence reaches 45%. NAFLD increases the risk of cardiovascular diseases by 3 times, the risk of death from them by 2 times and increases the risk of developing diabetes by 5 times. NAS occupies up to 20% of the structure of NAFLD and has a high potential for progression, and the violation of endogenous glycemic regulation and the development of DM2 accelerates the rate of disease progression.The goal was to determine the frequency of development of prediabetes (PD) and type 2 diabetes mellitus (T2DM) in NASH patients and the effect of impaired glycemic status on the clinical features of NASH.Materials and methods: 211 NASH patients were examined: 148 (70.1%) men, 63 (29.9%) women, 48.3 ± 10.2 years old. The diagnosis was established on the basis of clinical, laboratory, ultrasound and histological data. By enzyme immunoassay were determined: TNF-α, cytokeratin-18 fragments (CKF-18), insulin; were calculated HOMA-IR and NAFLD fibrosis score (NAFLD FS).Results and discussion. PD was detected in 39 (18.5%) patients, T2DM - in 33 (15.6%) patients. In PD patients, in contrast to patients with normoglycemia, the following indicators were significantly higher: waist circumference (WC), body mass index (BMI), cholesterol levels (Ch), LDL, ESR, TNF-α, NAFLD FS and lower albumin and platelet levels. In patients with T2DM, in contrast to those with normoglycemia, the following indicators were significantly higher: WC, BMI, alanine aminotransferase, alkaline phosphatase (APh), Ch, ESR, CKF-18 and NAFLD FS. In T2DM patients in contrast to those with PD, the following indicators were significantly higher: aminotransferases, APh and lower albumin level.Conclusions. Prediabetes and T2DM were detected with almost the same frequency among patients with NASH – in 18.5% and 15.6%, respectively. Disturbance of glycemic status was associated with a significance increase in waist circumference, markers of inflammation, dyslipidemia, fibrosis, hepatocytic necrosis, apoptosis, intrahepatic cholestasis and a decrease in albumin level.
Spondyloarthritis is a group of musculoskeletal inflammatory diseases, including axial and peripheral forms. The current classification of these diseases emphasizes the diagnostic importance of the well-known association between spondyloarthritis and inflammatory bowel diseases (Crohns disease and ulcerative colitis). According to many large clinical studies, both spondyloarthritis and inflammatory bowel diseases demonstrate increased cardiovascular risk, but the underlying mechanisms are not entirely clear. One of the possible ways to involve the cardiovascular system in these diseases is supposed to be the formation of endothelial vascular dysfunction developing in many inflammatory and non-inflammatory conditions. At the same time, endothelial dysfunction needs to be analyzed multidimensionally due to its participation in regulation of many processes, such as the providing of vascular tone, cell migration, angiogenesis, and hemostasis. This review examines the latest data on endothelial dysfunction in axial spondyloarthritis and inflammatory bowel diseases, and separately analyzes the studies of this phenomenon in patients with inflammatory bowel diseases-associated axial spondyloarthritis. Special attention is paid to modern laboratory and instrumental methods for assessing endothelial function and their potential diagnostic significance in clinical practice.
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