Цертолизумаб пегол в терапии ревматоидного артрита

The paper reviews the literature on the new tumor necrosis factor-α (TNF-α) antagonist certolizumab pegol (CZP). It considers the experience in using the drug in Russia within the framework of the RAPID 2 trial. The currently obtained material suggests that CZP has extended the capacities of RA treatment. The drug may be successfully used both alone and in combination with other disease-modifying anti-rheumatic drugs and it is effective in all degrees of disease activity. The agent is noted for a particularly rapid achievement of its therapeutic effect, early exhibits antidestructive properties, and enables prediction of the long-term results of therapy at a relatively early stage of its use. It is improbable that the administration of CZP versus other TNF-α antagonists in pregnancy may be safer since it does not seem to penetrate the placental barrier. Emphasis is laid on the most convenient method for administration of the drug, namely, its subcutaneous route at large intervals. In this case there may be rare local reactions.Представлен обзор литературы, посвященной новому антагонисту ФНО α - цертолизумабу пеголу (ЦЗП). Рассматривается опыт применения этого препарата в России в рамках исследования RAPID 2. Полученный к настоящему времени материал позволяет считать, что ЦЗП расширил возможности лечения РА. Он может успешно применяться как в виде монотерапии, так и в комбинации с другими базисными препаратами, эффективен при всех степенях активности болезни. Препарат отличается особенно быстрым достижением лечебного эффекта, рано проявляет антидеструктивные свойства, позволяет предсказать отдаленные результаты терапии на относительно раннем этапе назначения. Не исключено, что по сравнению с другими антагонистами ФНО α применение ЦЗП при беременности может оказаться более безопасным, поскольку он, по-видимому, не проходит через плацентарный барьер. Подчеркивается наиболее удобный для пациентов метод введения - подкожный, с большими интервалами. В таком случае наблюдаются редкие местные реакции

Russian registry of Infliximab.Impact of therapy on the functional status of patients with rheumatoid arthritis

Objective. To evaluate the functional state of rheumatoid arthritis (RA) patients receiving Infliximab therapy (IF) in real clinical practice and its efficiency. Subjects and methods. The analysis covered 225 patients receiving IF therapy, the follow-up duration in whom was 54 weeks. Disease activity was estimated by the DAS 28 index; functional status was assessed according to the Health Assessment Questionnaire (HAQ). The authors made an analysis of a Per-Protocol (PP) population (n = 154) at 54 weeks of treatment and an analysis that could consider the results of treatment (by the ACR and EULAR criteria) in patients who had been withdrawn before the control time - a LOCF (Last Observation Carried Forward analysis) population. Results. The mean age of the patients was 47.6±11.4 years; the duration of the disease was 7.8±6.4 years; DAS 28 activity scores were 6.6±1.1; the majority of patients had significant functional impairments (HAQ scores of 2.0±0.7), 86.7% of the patients had extraarticular manifestations; 79.6% were found to have rheumatoid factor (RF); the patients received an average of > 2 disease-modifying antirheumatic drugs (DMARDs). After 2 week-therapy, there was a reduction in RA activity by DAS 28 index in both the PP (from 6.7±1.1 to 4.0±1.4) and LOCF (6.6±1.1 and 4.2±1.4; p < 106) populations. Drug-induced remission (DAS 28 < 2.6) at 54 weeks was observed in 16.9 and 15.1% of the patients, respectively. Functional improvement was noted in the PP population: HAQ decreased from 2.0±0.7 to 1.7±0.7 scores by week 2; its reduction continued until week 14 (p < 0.05), by remaining stable later on. HAQ dropped from 2.0±0.7 to 1.2±0.7 scores in the LOCF population. At 54 weeks, normal population values of functional activity were achieved in 16.4%. Log regression analysis in the LOCF population indicated that the previous use of DMARDs and a short history of the disease were predictors of an ACR70 response to IF therapy [OR=1.61 (1.13-2.30), p = 0.008 and OR = 0.91 (0.84-0.98), p = 0.018, respectively]. RF seronegativity was a predictor for achievement of low RA activity [OR = 0.44 (0.23-0.84)]. The previous use of glucocorticoids failed to increase the probability of a good response to IF therapy and achievement of clinical remission [OR = 0.26 (0.11-0.60), p = 0.001]. Conclusion. Therapy with IF in combination with methotrexate or other DMARDs reduces RA activity and improves the functional capacities of patients with RA in real clinical practice

Efficiency of tocilizumab therapy for an exacerbation of systemic lupus erythematosus: A case report and a review of literature

Interleukin-6 (IL-6) is one of the major proinflammatory cytokines, which, by interacting with hepatocytes, induces the synthesis of a broad spectrum of acute phase inflammatory proteins. IL-6 plays an important role in the development and progression of systemic lupus erythematosus (SLE), participates in the differentiation of CD4/CD8 regulatory T lymphocytes and in the production of autoantibodies by B lymphocytes, and increases the survival of plasmablasts. Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody that neutralizes the pleiotropic effects of the cytokine. The use of this drug in SLE can have acceptable efficiency with the high inflammatory activity that is accompanied by fever, polyarthritis, polyserositis, skin lesions, and hemolytic anemia. The authors demonstrated the successful use of TCZ in a female patient with a documented diagnosis of SLE with a high activity (SLEDAI-2K-11). The use of the drug was justified by the prevalence of musculoarticular, constitutional (fever) disease, a high immunological activity (anti-DNA antibodies, 150 IU/ml; antinuclear factor, 1/1280 h; CRP, 88). This therapy could achieve complete relief of fever at day 2 after the first infusion of TCZ, a reduction, and subsequently complete relief of arthritis and normalization of laboratory blood parameters. TCZ has a satisfactory safety profile and may be considered as an alternative treatment for SLE when glucocorticoids, cytostatic agents, and rituximab are ineffective

Point mutation of tyrosine 759 of the IL-6 family cytokine receptor, gp130, augments collagen-induced arthritis in DBA/1J mice

<p>Abstract</p> <p>Background</p> <p>Knock-in mice (gp130F759) with a Y759F point mutation in gp130, a signal transducing receptor subunit shared by members of the IL-6 cytokine family, show sustained activation of STAT3, enhanced acute-phase or immune responses, and autoimmune arthritis. We conducted a detailed analysis of collagen-induced arthritis (CIA) in gp130F759 with a DBA/1J background (D/J.gp130F759).</p> <p>Methods</p> <p>We backcrossed gp130F759 to C57BL/6 and DBA/1J, and compared the pathologic changes, including occurrence of arthritis, in the two distinct genetic backgrounds. We analyzed CIA in D/J.gp130F759 and investigated the effects of methotrexate (MTX) on CIA.</p> <p>Results</p> <p>C57BL/6 background gp130F759 mice, but not D/J.gp130F759, spontaneously developed polyarthritis and glomerulonephritis. On the other hand, keratitis of the eyes only developed in D/J.gp130F759, indicating the influence of genetic background on disease development in gp130F759 mice. Resistance of the DBA/1J background against spontaneous arthritis urged us to examine CIA in D/J.gp130F759. CIA in D/J.gp130F759 was more severe, with greater bone destruction, than the control mice. After collagen immunization, splenomegaly and serum levels of rheumatoid factor and anti-DNA antibody were augmented in D/J.gp130F759. Bio-Plex analysis of serum cytokines revealed increased IL-12p40 and PDGF-BB before immunization, and increased levels of IFN-γ, IL-17, TNF-α, IL-9, and MIP-1β 8 days after the booster dose. IL-6 and PDGF-BB in D/J.gp130F759 showed distinct kinetics from the other cytokines; higher levels were observed after arthritis development. MTX partially attenuated the development of arthritis and inhibited bone destruction in D/J.gp130F759, with reduction of anti-type II collagen antibody levels, suggesting that MTX mainly affects antigen-specific immune responses in CIA.</p> <p>Conclusion</p> <p>The Tyr-759 point mutation of the IL-6 family cytokine receptor subunit, gp130, caused autoimmune disease, and this was also influenced by the genetic background. CIA in D/J.gp130F759 is useful for evaluating drugs in a relatively short period because sustained activation of STAT3 may enhance the disease symptoms.</p

Эффективност ь терапии тоцилизумабом обострения системной красной волчанки. Описание случая и обзор литературы

Interleukin-6 (IL-6) is one of the major proinflammatory cytokines, which, by interacting with hepatocytes, induces the synthesis of a broad spectrum of acute phase inflammatory proteins. IL-6 plays an important role in the development and progression of systemic lupus erythematosus (SLE), participates in the differentiation of CD4/CD8 regulatory T lymphocytes and in the production of autoantibodies by B lymphocytes, and increases the survival of plasmablasts. Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody that neutralizes the pleiotropic effects of the cytokine. The use of this drug in SLE can have acceptable efficiency with the high inflammatory activity that is accompanied by fever, polyarthritis, polyserositis, skin lesions, and hemolytic anemia. The authors demonstrated the successful use of TCZ in a female patient with a documented diagnosis of SLE with a high activity (SLEDAI-2K-11). The use of the drug was justified by the prevalence of musculoarticular, constitutional (fever) disease, a high immunological activity (anti-DNA antibodies, 150 IU/ml; antinuclear factor, 1/1280 h; CRP, 88). This therapy could achieve complete relief of fever at day 2 after the first infusion of TCZ, a reduction, and subsequently complete relief of arthritis and normalization of laboratory blood parameters. TCZ has a satisfactory safety profile and may be considered as an alternative treatment for SLE when glucocorticoids, cytostatic agents, and rituximab are ineffective.Интерлейкин 6 (ИЛ6) – один из основных провоспалительных цитокинов, который, взаимодействуя с гепатоцитами, индуцирует синтез широкого спектра белков острой фазы воспаления. ИЛ6 играет важную роль в развитии и прогрессировании системной красной волчанки (СКВ), принимает участие в дифференцировке CD4/CD8 T-лимфоцитов, Т-регуляторных клеток, продукции аутоантител В-лимфоцитами, повышает выживаемость плазмобластов. Тоцилизумаб (ТЦЗ) представляет собой гуманизированное антитело к рецепторам ИЛ6, которое нейтрализует плейотропные эффекты цитокина. Применение этого препарата при СКВ может обладать приемлемой эффективностью при высокой воспалительной активности, сопровождающейся лихорадкой, полиартритом, полисерозитом, поражением кожи и гемолитической анемией. Нами продемонстрировано успешное применение ТЦЗ у пациентки с достоверным диагнозом СКВ высокой степени активности (SLEDAI-2K-11). Назначение препарата обосновывалось превалированием суставно-мышечной, конституциональной (лихорадка) патологии, высоким уровнем иммунологической активности (антитела к ДНК – 150 Ед/мл, антинуклеарный фактор – 1/1280 h, СРБ – 88). Благодаря такой терапии удалось достигнуть полного купирования лихорадки ко 2-му дню после первой инфузии ТЦЗ, уменьшения, а в последующем и полного купирования артритов, нормализации лабораторных показателей крови. ТЦЗ имеет удовлетворительный профиль безопасности и может рассматриваться как альтернативный метод терапии СКВ при недостаточном эффекте глюкокортикоидов, цитостатиков и ритуксимаба

Инфликсимаб в российской клинической практике

The study of infliximab began (INF) in Russia in 2001. It was the first genetically engineered biological agent (GEBA) registered in our country to treat patients with rheumatoid arthritis (RA). With the advent of infliximab, a Russian biological rheumatoid arthritis therapy registry started its work. In October 2005, it was set up on the basis of GEBA centers founded in the leading rheumatology clinics of Russia. Objective: to generalize the Russian experience in using INF (its efficacy, tolerance, and side effects) in patients with RA in real clinical practice within the framework of a multicenter observational study. Subjects and methods. The register included patients with a valid diagnosis of RA in whom INF treatment was first started. The main indication for this was previous basic therapy failure. This investigation analyzed 396 patients receiving INF therapy. Prior to INF administration, all the patients were examined to identify whether they had possible latent tuberculosis, by applying chest X-ray study and Mantoux test. The European League Against Rheumatism criteria were used to evaluate the efficiency of INF therapy. The relationship between the therapeutic effects of the drug and its cumulative dose was specially used. The trend in X-ray progression was estimated using the Sharp method modified by van der Heijde. INF was given in a dose of 3 mg/kg by the classical regimen: at 0, 2, and 6 weeks, then every 8 weeks. The main assessment periods were at 22 and 46—54 weeks. Results. Analysis of the data of real clinical practice in Russia demonstrates that the use of INF in RA patients with the inadequate effect of traditional disease-modifying antirheumatic drugs (DMARDs) is able to cause a rapid and pronounced reduction in disease activity. There is significant evidence that the IFN-treated patients with RA had also suppressed bone destruction. INF treatment for early RA gives rise to remissions more frequently in the early stage of therapy than that for extensive-stage disease. INF was shown to have a clear dose-dependent effect: in the patients receiving more than 4 infusions of the drug, bone destruction was more noticeably suppressed than in those having its fewer infusions. In most cases, suppressed destruction was accompanied by clinical improvement. A significant therapeutic effect was seen when both an annual course of INF and average (5—7 infusions per year) doses of the drug were used. The results of the analysis suggest that the probable efficiency of INF therapy increases in RF-negative patients with lower baseline RA activity and fewer HAQ scores. INF was quiet satisfactorily tolerated and caused no unusual side effects. Conclusion. The Russian experience in using INF strongly suggests that it is effective in real practice in severe RA resistant to therapy with traditional DMARDs.Исследование инфликсимаба (ИНФ) в России началось в 2001 г. Он был первым генно-инженерными биологическим препаратом (ГИБП), зарегистрированным в нашей стране для лечения больных ревматоидным артритом (РА). С появлением ИНФ начал свою работу Российский регистр биологической терапии ревматоидного артрита (АРБИТР), созданный в октябре 2005 г. на базе центров ГИБП, организованных в ведущих ревматологических клиниках России. Цель исследования — обобщение российского опыта применения ИНФ (эффективность, переносимость и побочные эффекты) у больных РА в реальной клинической практике в рамках многоцентрового наблюдательного исследования. Материал и методы. В регистр включали больных с достоверным диагнозом РА, которым впервые начато лечение ИНФ. Основным показанием для этого была неэффективность предшествующей базисной терапии. В настоящем исследовании проанализировано 396 больных, получавших терапию ИНФ. Всем больным до назначения ИНФ проводились обследование для выявления возможного латентного туберкулеза: рентгенография грудной клетки и проба Манту. Для оценки эффективности терапии ИНФ использовали критерии EULAR. Специально изучалась зависимость лечебного эффекта от суммарной дозы препарата. Оценка динамики рентгенологического прогрессирования проводилась по методу Sharp в модификации Van der Heijde. ИНФ назначался в дозе 3 мг/кг по классической схеме: 0; 2; 6-я недели, далее каждые 8 нед. Основными периодами оценки результатов терапии были 22-я и 46-54-я недели. Результаты исследования. Анализ данных реальной клинической практики в России демонстрирует, что назначение ИНФ больным РА с недостаточным эффектом традиционных БПВП способно в большинстве случаев привести к быстрому и выраженному уменьшению активности заболевания. Достоверно установлено также торможение костной деструкции у больных РА, получающих ИНФ. Лечение ИНФ при раннем РА приводит к более частому развитию ремиссий на начальном этапе терапии по сравнению с результатами при развернутой стадии болезни. Показан четкий дозозависимый эффект ИНФ: у пациентов, получивших более 4 инфузий препарата, костная деструкция тормозилась более отчетливо по сравнению с получившими меньшее количество инфузий. В большинстве случаев торможение деструкции сочеталось с клиническим улучшением. Выраженный терапевтический эффект отмечен при назначении как годового курса ИНФ, так и «средних» (5—7 инфузий за год) доз препарата. Результаты нашего анализа свидетельствуют о том, что вероятность эффективности терапии ИНФ возрастает у РФ-негативных пациентов, при относительно менее высокой исходной активности РА и более низкой величине HAQ. Переносимость ИНФ была вполне удовлетворительной, необычных побочных эффектов не зарегистрировано. Заключение. Российский опыт применения ИНФ убедительно свидетельствует о его эффективности в реальной практике при тяжелом РА, резистентном к терапии традиционными БПВП

GOLIMUMAB SAFETY ACCORDING TO CLINICAL FINDINGS

The review analyzes trials dealing with the safety of golimumab (GLM)  used in rheumatology.  This drug was the latest Contact: Galina Lukina;[email protected] Поступила 12.05.14tumor necrosis factor α (TNF-α) inhibitor introduced  into clinical practice and therefore the estimation of its tolerability is particularly relevant. The data obtained in large-scale clinical trials suggest that GLM has a good safety profile. The most common  adverse events (AE) were infections, more often mild. The rate of infections was higher with the use of GLM 100 mg than with that of 50 mg. The overall cancer rate did not increase during a follow-up of less than 160 weeks. However, the rate of lymphomas in patients receiving GLM 100 mg proved to be higher than in those taking GLM 50 mg, in the general population, and in the placebo group in particular. AE were evenly distributed among patients with rheumatoid  arthritis, psoriatic arthritis, or ankylosing spondylitis. Overall, the findings are in agreement with the data on the safety of previously used TNF-α inhibitors. No fundamentally new AE have been encountered. It is necessary to accumulate  data on the use of GLM in real clinical practice, which will be able to more objectively define its place in the current therapy of rheumatic diseases

Certolizumab pegol in therapy for rheumatoid arthritis

The paper reviews the literature on the new tumor necrosis factor-α (TNF-α) antagonist certolizumab pegol (CZP). It considers the experience in using the drug in Russia within the framework of the RAPID 2 trial. The currently obtained material suggests that CZP has extended the capacities of RA treatment. The drug may be successfully used both alone and in combination with other disease-modifying anti-rheumatic drugs and it is effective in all degrees of disease activity. The agent is noted for a particularly rapid achievement of its therapeutic effect, early exhibits antidestructive properties, and enables prediction of the long-term results of therapy at a relatively early stage of its use. It is improbable that the administration of CZP versus other TNF-α antagonists in pregnancy may be safer since it does not seem to penetrate the placental barrier. Emphasis is laid on the most convenient method for administration of the drug, namely, its subcutaneous route at large intervals. In this case there may be rare local reactions

Combination therapy for rheumatoid arthritis with rituximab and leflunomide(preliminary results of the Russian ARBITR Registry)

The paper analyzes the efficiency and tolerability of a combination of rituximab (RTM) and leflunomide (LEF) for the treatment of rheumatoid arthritis (RA) versus the conventional combination of RTM and methotrexate (MT). The results of 24-week therapy were assessed in the RA patients included into the Russian Biological Therapy Register. A good effect of therapy was achieved in 31.8% of the patients who had received RTM+LEF (p = 0.1). The development of clinical remissions in RA was observed at a practically equal frequency of 13.6 and 11.7%, respectively. The doses of glucocorticoids and nonsteroidal anti-inflammatory drugs used in concurrent anti-inflammatory therapy could be substantially reduced in both groups. In both groups, the rate of side effects was very equal: 21.7% for the RTM+LEF group and 25.7% for the RTM+MT group. Thus, the combination therapy of RTM and LEF in real clinical practice is not considerably different from the most commonly used combination of RMT and MT in efficiency and tolerability and may be successfully used if there are any contraindications to the use of MT