Репозиторий Университета

© 2018, The Author(s). Efficacy and safety of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, were demonstrated in juvenile idiopathic arthritis (JIA) with polyarticular course (pJIA) in the CHERISH trial. This observational, III phase study evaluated long-term treatment of TCZ in pJIA patients was conducted by members of the Pediatric Rheumatology International Trials Organization (PRINTO) from Poland and Russia. Forty-one patients, who had completed the CHERISH core study (104 weeks), were extensionally treated with TCZ (8 mg/kg, intravenous infusion every 4 weeks). Total treatment time was from 131 to 193 weeks. The long-term safety (the primary endpoint) and efficacy were evaluated. All patients achieved ACR70 response in the core study and continued to achieve at least ACR50 response up to week 24 of this study. The safety population comprised 46.41 patient-years (PY). Rates per 100 PY of adverse (AEs) and serious events (SAEs) were 181.0 and 6.46, respectively. Pharyngitis and respiratory tract infections were the most common AEs. Except one AE (severe neutropenia), all others were classified as mild (24.4%) or moderate (29.3%). The incidence of SAEs was low (7.3%). No new safety findings were observed. The safety profile of over 2.5-year treatment with TCZ is consistent with the pre-marketing CHERISH clinical trial. Presented data and continued efficacy response support the use of TCZ in pJIA. EUDRACT No: 2011-001607-12. https://clinicaltrials.gov/ct2/show/study/NCT01575769?term=ML27783.

© 2018 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología Case history of a small girl outlet with epilepsy, followed by scleroderma skin damage and uveitis, neurovasculitis with white matter foci in brain on the side of skin lesion in two months, immunologic disease activity. Resistance to conventional immunosuppressive therapy forced us to initiate the treatment with tocilizumab. It was well tolerated and led to significant improvement of brain, ocular and skin manifestations.

© 2018 Voprosy Sovremennoi Pediatrii - Current Pediatrics. All rights reserved. Background. Infections are the main cause of death for patients with autoimmune rheumatic diseases. In adult patients with rheumatoid arthritis (RA), mortality caused by respiratory infections is 2-5 times higher than in the population. One of the frequent infectious complications in the course of treatment with tocilizumab, the first-choice drug for treating systemic juvenile idiopathic arthritis (sJIA), is pneumonia characterized by a poor clinical picture, normal values of laboratory indices of the disease activity (ESR, C-reactive protein) with pronounced changes in the lungs revealed by computed tomography. In case of acute respiratory infection in children with systemic JIA, immunosuppressants and genetically engineered biological preparations (GEBP) are discontinued. This often leads to an exacerbation of the underlying disease and the progression of a pathological process. At present, vaccination against pneumococcal infection in Russia is not included in the standard for managing patients with rheumatic diseases. Studies of the safety and efficacy of vaccination with 13-valent pneumococcal conjugate vaccine (PCV) in patients with sJIA receiving genetically engineered biological preparations were not conducted. Clinical Case Description. The article shares the experience of vaccination of a girl aged 9 years with a 13-valent PCV that was conducted in the course of a scientific investigation, which studied the efficacy and safety of vaccination of children with systemic JIA prior to prescription of GEBP tocilizumab. Vaccination did not cause a deterioration in the course of the main disease (1 month), led to a reduction in the incidence of acute respiratory infections (from 4 to 1 time within 6 months before and after vaccination), and discontinuation of antibacterial drugs within 6 months after vaccination. Conclusion. The safety of a 13-valent PCV in a child with sJIA and a decrease of the incidence of respiratory diseases after vaccination, their complications, and the use of antibacterial drugs have been shown.

© 2018 Media Sphera Publishing Group. All rights reserved. According to modern ideas, chronic low-grade inflammation, which development is associated with uncontrolled activation of both innate and adaptive immunity, plays a fundamental role in all stages of the atherosclerotic process. The contribution of inflammation to the development of atherosclerotic vascular lesions attracts attention to the similarity of the mechanisms of immunopathogenesis of atherosclerosis and classic inflammatory rheumatic disease - rheumatoid arthritis. In the aspect of participation in the pathogenesis of atherosclerotic vascular lesions and as a promising therapeutic "target" of particular interest is interleukin-1β (IL-1β), which plays an important role in the development of many acute and chronic immunosuppressive diseases. The mechanisms of atherosclerosis associated with IL-1β determine the ability of cholesterol crystals and other "Pro-atherogenic" factors to induce the synthesis of IL-1β by activating NLRP3 inflammasome. The mechanisms of atherosclerosis associated with IL-1β determine the ability of cholesterol crystals and other "proatherogenic" factors to induce the synthesis of IL-1β by activating NLRP3 inflammasome. Convincing evidence for the role of inflammation in development of atherosclerosis in General and good prospects of anti-inflammatory therapy in particular obtained in a randomized placebo-controlled study called CANTOS (Canakinumab Anti-inflammatory Thrombosis Otcomes Study), which studied the effectiveness of treatment with monoclonal antibodies to IL-1β canakinumab (Novartis International AG) in patients with severe atherosclerotic vascular lesions as a new approach to secondary prevention of cardiovascular complications. The results of CÀNTOS research, as well as the experience gained in rheumatology in regard to cardiovascular effects of innovative antiinflammatory drugs, have great importance for the improvement of secondary prevention of atherosclerosis-related cardiovascular complications.

© 2018 Ima-Press Publishing House. All rights reserved.  The clinical efficacy and safety of interleukin-6 (IL-6) receptor blockade have been well studied, but the data on the impact of therapeutic inhibition of IL-6 on B cells are scarce and contradictory. Preliminary reports have shown that B cell function and a humoral immune response may be modulated by an IL-6 receptor inhibitor. Objective: to assess the effect of 12-month tocilizumab (TCZ) therapy on B-cell phenotype and gene expression in RA and to analyze the association between B-cell subsets and RA activity. Subjects and methods. Examinations were made in 24 active RA patients (20 women and 4 men) (median age, 55 [49; 64] years; disease duration, 72 [24; 108] months; DAS28 5.8 [5.3; 6.3]; the patients were seropositive for rheumatoid factor (RF) (100%) and for anti-cyclic citrullinated peptide antibodies (87.3%). The patients received TCZ 8 mg/kg every 4 weeks. After 12 months of therapy, 54% of patients were categorized as good responders, 46% as moderate responders according to the EULAR response criteria. A control group consisted of 29 volunteers (21 women and 8 men; median age, 58.5 [53.0; 62.0] years). Peripheral blood lymphocytes were immunophenotyped at the time of enrollment and after 12 months. The absolute and relative counts of CD19+B lymphocytes, memory B cells (CD19+CD27+), non-switched memory B cells (CD19+IgD+CD27+), switched memory B cells (CD19+IgDCD27+), naive (CD19+IgD+CD27-), double-negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38++CD27) B cells, plasma cells (CD19+CD38+), and plasmablasts (CD19+CD38+++IgD-CD27+CD20-) were estimated using multicolor flow cytometry. Results and discussion. The relative and absolute counts of memory B cells (CD19+CD27+) (1.3 [0.9; 1.7]%, 0015 [0.001; 0.003]•10 9 /l), switched memory B cells (CD19+IgD-CD27+) (6.8 [3.6; 11.6]%, 0.01 [0.005; 0.02]•10 9 /l), and the absolute number of transitional B cells (CD19+CD38++CD10+IgD+CD27-) (0.00009 [0; 0.00028]•10 9 /l) were found to be lower in RA patients than in donors: 2.2 [1.1; 3.0]%, 0.003 [0.001; 0.007]•10 9 /l; 12.8 [9.3; 17.0]%, 0.02 [0.01; 0.04]•10 9 /l; 0.0001 [0; 0.0003]•10 9 /l, respectively (p<0.05 for all cases). After 12 months of TCZ therapy initiation, there were decreases in the relative and absolute counts of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) from 0.15 [0.1; 0.3] to 0.1 [0.01; 0.1]% and from 0.0003 [0.00007; 0.004]•10 9 /l to 0.0001 [0; 0.0003]•10 9 /l, respectively (p<0.05). At the same time, the relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) remained lower in RA patients than in donors: 1.0 [0.7; 1.2] and 2.2 [1.1; 3.0]%; 0.001 [0.006; 0.003]•10 9 /l and 0.003 [0.001; 0.007]•10 9 /l; 3.1 [1.1; 4.2] and 12.8 [9.3; 17.0]%; 0.003 [0.002; 0.006]•10 9 /l and 0.02 [0.01; 0.04]•10 9 /l, respectively (p<0.05 for all cases). Following 12 months of TCZ therapy, the numbers of other B-cell subpopulations were not considerably altered. When included in the study, the patients with RA showed correlations between the absolute count of memory B cells (CD19+CD27+) and the level of C-reactive protein (r=0.50; p<0.05); between the absolute count of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) and the level of RF (r=0.41 and r=0.52; p<0.05). There were no correlations of B cell subsets with clinical and laboratory findings after 12 months of TCZ initiation. Conclusion. Immunophenotyping of peripheral blood B lymphocyte subsets showed the lower relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) in RA patients than in healthy donors. The found correlations between the counts of memory B cells and plasmablasts and the values of laboratory parameters in patients with high RA activity may suggest that B lymphocytes are involved in the pathogenesis of RA. There was a decline in plasmablast levels after 12 months of TCZ therapy.

© 2018 Publishing House of the Union of Pediatricians. All rights reserved. Background. To assign genetically engineered biologic drugs, we need data on the predictors for response to therapy. Prognostic factors for the response to tocilizumab in patients with juvenile idiopathic arthritis (JIA) without systemic symptoms are poorly studied. Objective. Our aim was to reveal early predictors for the response to tocilizumab therapy in patients with JIA without systemic symptoms. Methods. A retrospective cohort study enrolled patients with JIA without systemic symptoms who received tocilizumab therapy between July 2009 and August 2017. We assessed the association between the initial demographic, clinical, and laboratory parameters in patients and the best response (according to the ACR90 criteria) to treatment after a year. Results. The study included 95 (girls 85%) patients; the mean age was 10.3 (6.0; 13.6). During the first year of therapy, 71 (75%), 55 (58%), 38 (40%), and 22 (23%) patients achieved the improvement according to ACR30/50/70/90 criteria, respectively; 22 (23%) patients reached disease inactive stage according to the Wallace criteria. When performing multivariate analysis, the following improvement predictors were revealed based on the ACR90 criteria after a year of treatment: decrease in serum C-reactive protein level during the first month of therapy [odds ratio (OR) 1.024; 95% confidence interval (CI) 1.007-1.051], decrease in disease activity score on the visual analogue scale according to the parent/patient assessment (OR 1.048; 95% CI 1.005-1.105), early onset of the disease (OR 0.38; 95% CI 0.16-0.72), persistent oligoarthritis according to the ILAR (OR 9.9; 95% CI 1.5-109.3). During the first year of tocilizumab administration, neutropenia was registered in one patient, leukopenia - in three cases, and urticaria - in one case. Conclusion. The variant of JIA, the age at the disease onset, and the disease course pattern in the first month of tocilizumab therapy are the predictors of treatment efficacy throughout the year.

© 2018 Ima-Press Publishing House. Giant cell arteritis (GCA), formerly known as Horton's disease, is among the most common diseases from a group of systemic vasculitides; its clinical significance is complemented with the potential involvement of the coronary arteries, aorta, and cranial arteries with development of ischemic optic neuropathy if there is no timely treatment that results in rapid and irreversible visual loss. The elderly age of patients is one of the key aspects of GCA. Therefore, the disease is often accompanied by various comorbidities that have considerable impact on the choice of a treatment regimen and limit the use of standard therapy with glucocorticoids (GCs). The complications due to GC treatment can be competitive in severity with GCA, especially in elderly multimorbid patients. Progress in rheumatology due to the introduction of biological agents (BAs) has created the preconditions for the development of a new area of pharmacotherapy for GCA associated with interleukin 6 (IL6) inhibition using tocilizumab (TCZ). According to the results of two randomized placebocontrolled trials (RPCTs), which were published in 2016, the rate of remission with TCZ treatment was significantly higher in patients with GCA than that in the placebo group (p = 0.03-0.0001), as is relapse-free survival after 52 weeks of TCZ treatment (85 and 20%, respectively; p = 0.001), the incidence of serious adverse events (AE) was 14-35%. In 2017, the results of Phase III GiACTA RPCT became the basis for approval of the use of TCZ for the treatment of GCA in the United States and Europe. The authors present their own results of a small prospective study of TCZ in 7 patients with active GCA with severe comorbidity, including multimorbidity, that potentially increases the risk for AE due to GC therapy. The mean age of the patients was 71.3}7.6 years; among them there was one man and 6 women. The administration of TCZ in a monthly dose of 2.3-8.8 mg/kg for 1-10 months with a cumulative dose of 10-58.1 mg/kg could reduce the mean daily dose of prednisolone to 15 (5-32.5) mg, thereby preventing the development or progression of AE, and all the 7 patients could rather rapidly achieve GCA remission. A recurrence after therapy discontinuation was noted in one patient. TCZ treatment was accompanied by serious AE (purulent elbow bursitis); and other two patients had AE a few months after TCZ discontinuation. There were no fatal outcomes. Thus, the presented results suggest that the use of IL6 inhibitors in patients with GCA, including those with severe comorbidity, can be regarded as a potentially effective innovative (off-label) treatment strategy with an acceptable safety profile. The further expansion of an evidence base and the clarification of the medical and economic aspects of TCZ treatment in some groups of GCA will help justify the choice of BAs.

Авторами рассмотрены современные аспекты лечения неспецифического аортоартериита (НАА) у детей. Освещены вопросы патогенеза, клинической картины, основных принципов лечения болезни Такаясу в детском возрасте, подходы к оценке эффективности и безопасности проводимой базисной терапии. Представлены алгоритм базисной терапии детей с НАА и проблемы хирургического лечения. Наиболее эффективным является комплексный подход к лечению, подразумевающий назначение в активной фазе заболевания противоспалительной иммуносупрессивной терапии глюкокортикостероидами и цитостатиками, а при неэффективности - использование генно-инженерной биологической терапии.

Авторами рассмотрены современные аспекты лечения неспецифического аортоартериита (НАА) у детей. Освещены вопросы патогенеза, клинической картины, основных принципов лечения болезни Такаясу в детском возрасте, подходы к оценке эффективности и безопасности проводимой базисной терапии. Представлены алгоритм базисной терапии детей с НАА и проблемы хирургического лечения. Наиболее эффективным является комплексный подход к лечению, подразумевающий назначение в активной фазе заболевания противоспалительной иммуносупрессивной терапии глюкокортикостероидами и цитостатиками, а при неэффективности - использование генно-инженерной биологической терапии.