Актуальные вопросы применения ингибиторов фактора некроза опухоли α при ревматоидном артрите

The use of tumor necrosis factor (TNF) а inhibitors in combination with methotrexate remains the basic method for treating active rheumatoid arthritis (RA). This line in antirheumatic therapy is rapidly developing. A number of unsolved issues associated with the selection of patients (particularly at the early stage of RA) to be treated with TNF а antagonists, the prediction of its efficiency, the study of comparative aspects of therapy are on the agenda. The Russia's emergence of the latest TNF а inhibitor adalimumab that has unquestioned merits opens new vistas for the treatment of RA.Применение ингибиторов фактора некроза опухоли (ФНО) а в комбинации с метотрексатом остается основным методом лечения активного ревматоидного артрита (РА). Это направление в противоревматической терапии стремительно развивается. На повестке дня - ряд нерешенных вопросов, связанных с отбором пациентов (особенно на ранней стадии РА) для лечения антагонистами ФНО а, прогнозированием его эффективности, изучением сравнительных аспектов терапии. Появление в России самого современного ингибитора ФНО а - адалимумаба, обладающего неоспоримыми достоинствами, открывает новые перспективы в лечении РА

Нимесулид при ревматоидном артрите

Many patients with rheumatoid arthritis (RA) continue symptomatic treatment with anesthetics despite the progress in treating this disease, which is associated with improved methods for its early diagnosis and pathogenetic therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) remain a main class of analgesics used in RA. NSAIDs are an important component of RA treatment and should be administered in all cases of joint pain. Their administration at disease onset and in undifferentiated arthritis when carrying out a diagnostic search and selecting a concept of use of disease-modifying antirheumatic drugs (DMARDs) is of basic importance. NSAID therapy reduces patients’ distress and quality of life before DMARDs show their activity, considerably reduce disease activity, and relieve pain. This review considers the important aspects of using NSAIDs in RA. Nimesulide is one of the most popular NSAID representatives; its advantages and disadvantages are shown; particular emphasis is placed on its safety. Analysis of the data available in the literature has shown that the hepatotoxicity of nimesulide is not higher than that of many other representatives of the NSAID class. Although the fact that nimesulide may be responsible for menacing cardiovascular events is being investigated, none of the recent large trials of nimesulide has recorded a significant increase in the rate of cardiovascular events during its long-term use.У многих больных ревматоидный артритом (РА) сохраняется потребность в приеме симптоматических обезболивающих препаратов, несмотря на успехи в лечении этого заболевания, связанные с совершенствованием методов его ранней диагностики и патогенетической терапии. Основным классом анальгетиков, используемых при РА, остаются нестероидные противовоспалительные препараты (НПВП). НПВП являются важным компонентом лечения РА и должны применяться во всех случаях суставной боли. Особое значение имеет их назначение в дебюте болезни и при недифференцированном артрите, когда ведется диагностический поиск и выбирается концепция применения базисных противовоспалительных препаратов (БПВП). Терапия НПВП уменьшает страдания и улучшает качество жизни больных до того момента, когда проявится действие БПВП и будет достигнуто значительное снижение активности болезни, в том числе исчезновение боли. В настоящем обзоре рассмотрены важные аспекты применения НПВП при РА. Одним из наиболее популярных представителей НПВП является нимесулид, представлены достоинства и недостатки, этого препарата, особое внимание уделено проблеме его безопасности. Как показал анализ данных литературы, гепатотоксичность нимесулида не выше, чем у многих других представителей класса НПВП. Хотя проблема развития опасных кардиоваскулярных осложнений при использовании нимесулида продолжает изучаться, ни в одном из крупных исследований нимесулида, проведенных в последнее время, не зафиксировано значимого повышения частоты кардиоваскулярных осложнений на фоне его длительного приема

CHANGES OF CYTOKINE LEVELS DURING THERAPY WITH METHOTREXATE AND ADALIMUMAB IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS (REMARCA STUDY)

Objective: to estimate changes in cytokine profile versus disease activity in patients with early rheumatoid arthritis (RA) who use methotrexate (MTX) and adalimumab (ADA) in accordance with the treat-to-target concept. Subjects and methods. Forty-five patients (35 women; median age 53.5 [46; 59.5] years) with early RA (median dura- tion 7.0 [4.0; 11.5] months; DAS28 5.8 [4.9; 6.4]; rheumatoid factor positivity (RF+) 91%; anti-cyclic citrullinated peptide antibody positivity (ACCP) + 96%) were examined. In all the patients, MTX as the first agent was subcuta- neously used in a dose of 10 mg/week with its rapid escalation up to 20-25 mg/week. Serum cytokine concentrations were determined using the xMAP multiplexing technology before and 12 and 24 weeks after therapy. Results. Following 12 weeks of therapy, DAS28 mean value decreased to 4.33 [3.5; 5.2] (p < 0.05 vs baseline). Twenty- nine (64.4%) patients responded to treatment. It was decided to continue MTX monotherapy in 23 patients (a monotherapy group) and in 22 patients ADA was added to therapy due to its inadequate effect in accordance with the standard regimen (a combined therapy group). At 24 weeks, mean DAS28 was 2.9 [2.1; 3.6] and 19 (82.6%) patients responded to treatment in the monotherapy group. In the combined therapy group, DAS28 was 3.4 [3.2; 4.4]; nearly 30% of the patients achieved remission/low disease activity and the number of patients with the high activity of a pathological process also declined significantly (from 59.1 to 13.6%). At 12 weeks, the monotherapy group showed reduction of the level of proinflammatory (interleukin-6 (IL-6), IL-17, tumor necrosis factor-α (TNF-α)), anti-inflammatory (IL-4, IL-5, IL-9, IL-13) cytokines, chemokines (interferon induced protein-10 (IP-10)), and vascular endothelial growth factors (VEGF) (p<0.05); at 24 weeks, there were reductions in IL-6, IL-9, and IL-10, and transforming GF-bb and an increase in IL-10 concentration (p<0.05). At 12 weeks of MTX therapy, the combined therapy group displayed a reduction in IL-6, IL-1Pa, IP-10 (p<0.05); at 24 weeks of treatment (12-week ADA administration) there were decreases in proinflammatory (IL-12), anti-inflammatory (IL-9) cytokines, chemokines (IP-10, monocyte chemoattractant protein, and macrophageal inflammatory protein-1β), VEGF and an elevation of IL-10. Conclusion. Thus, the results of the investigation suggest the high clinical efficiency of therapy with subcutaneous MTX, which is associated with the lower levels of a number of proinflammatory cytokines, chemokines, and growth factors. ADA treatment is also accompanied by decreased disease activity and positive changes in the cytokine profile, by exerting a higher impact on the level of chemokines and growth factors

Диацереин при остеоартрозе: открытое сравнительное исследование

Osteoarthritis (OA) is a degenerative joint disease that is accompanied by cartilage destruction, synovial membrane inflammatory changes, and subchondral bone remodeling.Objective: to perform comparative evaluation of the efficiency of knee OA treatment with diacerein, hyaluronic acid, and nonsteroidal antiinflammatory drugs at short- and long-term follow-up.Patients and methods. An open-label comparative enrolled 192 patients with knee arthritis: 68.5% women and 31.5% men (mean age, 52.7±1.79 years; mean disease duration, 7 years). The patients were divided into three groups matched for gender, age, and disease duration: Group 1 (n=63) took diacerein 100 mg/day; Group 2 (n=65) received intraarticular hyaluronic acid 2 ml thrice at an interval of 7 days; Group 3 (n=64) had diclofenac 75 mg/day. The patients of all the three groups had a similar magnitude of its symptoms and Kellgren grade. Magnetic resonance imaging (MRI) and arthroscopic examination of the knee joint were performed to assess the results of treatment in the patients.Results. To evaluate the chondroprotective effect of the drugs, the authors used their proposed arthroscopic and MRI criteria (sensitivity, 89.7%; specificity, 93.1%) that allow abnormally changed and normal cartilages to be identified. At months 2 of treatment, all the three drugs ensured a considerable pain intensity reduction that persisted till 12 weeks. The important benefit of diacerein and hyaluronic acid was their aftereffect for further 3 months.Остеоартроз (ОА) – дегенеративное заболевание суставов, которое сопровождается деструкцией хряща, воспалительными изменениями в синовиальной оболочке, ремоделированием субхондральной кости.Цель исследования – сравнительная оценка эффективности лечения ОА коленного сустава диацереином, препаратами гиалуроновой кислоты и НПВП при краткосрочном и длительном наблюдении.Пациенты и методы. В открытое сравнительное исследование включено 192 больных артрозом коленного сустава: 68,5% женщин и 31,5% мужчин; средний возраст – 52,7±1,79 года; средняя длительность заболевания – 7 лет. Больные были разделены на три группы, сопоставимые по полу, возрасту и длительности заболевания: 1-я группа (n=63) получала диацереин 100 мг/сут; 2-я группа (n=65) – внутрисуставное введение препаратов гиалуроновой кислоты по 2 мл трижды с интервалом в 7 дней; 3-я группа (n=64) – диклофенак 75 мг/сут. Пациенты всех трех групп имели схожую выраженность симптомов и стадию по Келлгрену. Для оценки результатов лечения больным проводили магнитно-резонансную томографию и артроскопическое исследование коленного сустава.Результаты. Для определения хондропротективного действия препаратов использовали предложенные нами артроскопические и МР-критерии (чувствительность – 89,7%, специфичность – 93,1%), которые позволяют идентифицировать патологически измененный и нормальный хрящ. Все три препарата обеспечили значительное снижение выраженности боли ко 2-му месяцу лечения, которое сохранялось до 12 нед. Важным преимуществом диацереина и препаратов гиалуроновой кислоты явилось наличие эффекта последействия в течение последующих 3 мес

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

Выраженный и быстрый терапевтический эффект тофацитиниба в комбинации с подкожным метотрексатом у пациентки с ревматоидным артритом, имеющей факторы неблагоприятного прогноза, резистентной к стандартным базисным средствам и генно-инженерным биологическим препаратам (клинический случай)

Today, it is generally accepted that it is necessary to achieve clinical remission in rheumatoid arthritis (RA) or as minimum a low disease activity. The paper describes a clinical case of a female patient diagnosed with RA who was observed to have inefficiency of standard disease-modifying antirheumatic therapy with methotrexate 25 mg/week, secondary inefficiency of tumor necrosis factor-α inhibitors (adalimumab), and inefficiency/poor tolerance of the interlukin-6 receptor antagonist tocilizumab. This determined the need to use fofacitinib (TOFA), a drug with another mechanism of action. TOFA is the first agent from a new group of immunomodulatory and anti-inflammatory drugs, intracellular kinase inhibitors. Disease remission could be achieved during therapy with TOFA, which enables one to consider this synthetic drug as a therapy option that potentially competes with therapy with biologicals.В настоящее время общепризнана необходимость достижения при ревматоидном артрите (РА) клинической ремиссии или как минимум низкой активности болезни. Представлено клиническое наблюдение пациентки с диагнозом РА, у которой наблюдались неэффективность стандартной базисной противовоспалительной терапии метотрексатом (МТ) в дозе 25 мг/нед, вторичная неэффективность ингибиторов фактора некроза опухоли α (адалимумаба) и неэффективность/плохая переносимость антагониста рецепторов интерлейкина 6 тоцилизумаба. Это определило необходимость назначения тофацитиниба (ТОФА) – препарата с другим механизмом действия. ТОФА – первое лекарственное средство из новой группы иммуномодулирующих и противовоспалительных препаратов, ингибиторов внутриклеточных киназ. На фоне терапии ТОФА была достигнута ремиссия заболевания, что дает основание рассматривать этот синтетический препарат как метод терапии, потенциально конкурирующий с терапией биологическими агентами

ASSOCIATION BETWEEN CLINICAL MANIFESTATIONS AND ULTRASONIC SIGNS OF INFLAMMATION IN PATIENTS WITH RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease characterized by chronic inflammation of the synovial membrane and a wide range of extra-articular (systemic) manifestations. The main goal of RA therapy is to achieve low disease activity or clinical remission. Power Doppler (PD) ultrasonography (USG) can significantly distinguish between active synovitis (hypervascularization of the synovial membrane) and inactive synovial proliferation.Objective: to investigate the association between the ultrasonic signs of active inflammation and the clinical and laboratory parameters of disease activity in patients with RA.Subjects and methods. The investigation included RA patients followed up at the V.A. Nasonova Research Institute of Rheumatology within the first Russian strategic study of pharmacotherapy for RA – REMARCA (Russian invEstigation of MethotrexAte and biologicals for eaRly aCtive Arthritis). A total of 105 RA patients (mean age 51 years), among whom 80% were rheumatoid factor (RF)-positive and 75% were anti-cyclic citrullinated peptide (ACCP)-positive, were examined. In all the patients, methotrexate (metoject, MEDAC, Germany) as the first diseasemodifying anti-rheumatic drug was subcutaneously injected in an initial dose of 10 mg/week with its rapid escalation up to 20–25 mg/week. Then the therapy was added by biologicals as the need arose. The clinical and laboratory parameters were analyzed immediately before and then 12, 24, 36, and 48 weeks following treatment. Therapeutic efficacy was evaluated using the European League Against Rheumatism (EULAR) criteria and activity indices (DAS28, CDAI, and SDAI). USG of eight articular areas (the wrist, second and third metacarpophalangeal, second and third proximal interphalangeal, second and fifth metatarsophalangeal articulations) in the hand and foot of the clinically dominant side was carried out in all the patients prior to treatment and at 12, 24, 36, and 48 weeks after its initiation. Semiquantitative gray-scale (GS) assessment and PD USG were performed according to the OMERACT criteria.Results and discussion. Weak correlations were found between USG parameters and DAS28, SDAI, and CDAI. After 48-week therapy, the signs of active synovitis were absent in 54 patients and persisted in 51, as evidenced by PD USG. The differences in clinical, laboratory, and ultrasonic parameters were analyzed in relation to USG evidence for active inflammation following 48 weeks of treatment. There were significant differences in GS and PD scores throughout the follow-up period; there were also differences in C-reactive protein levels at 12 and 48 weeks of therapy. No differences were found in clinical activity indices.Conclusion. The investigation provides support for the important role of USG in assessing the activity of synovitis in RA

THE TIME COURSE OF CHANGES IN BIOMARKER LEVELS AND THE ULTRASONIC SIGNS OF INFLAMMATION IN PATIENTS WITH RHEUMATOID ARTHRITIS

Subclinical inflammation detected by ultrasonography (USG) promotes the progression of joint injury in patients with rheumatoid arthritis (RA). Performed studies ambiguously assess the association of disease activity indices with the Doppler ultrasonic signs of synovitis and the serum concentration of cytokines in patents with RA.Subjects and methods. Thirty-eight patients with early RA, who were followed up within the framework of the REMARCA program, were examined. All the patients' therapy was started with subcutaneous methotrexate (MTX) with its rapid dose escalation up to 20–30 mg/week and assessment of the achievement of the treatment goal (low disease activity or remission) every 3 months according to the reason why a decision had been made to add biological agents to the therapy. Clinical and standard laboratory parameters with calculated disease activity indices (DAS28, CDAI, SDAI) were analyzed immediately before and 12, 24, and 48 weeks after treatment. Blood cytokine concentrations were determined by the xMAP multiplex technology before and then 12 and 24 weeks after therapy. USG of 8 joint areas of the hands and feet was undertaken prior to and then 12, 24, and 48 weeks following treatment. Gray-scale synovial hypertrophy and synovial power Doppler (PD) signals were rated for each joint area (0 to 3 scores).Results and discussion. During the drug therapy, all the patients showed improvement with a reduction in activity indices (DAS28, SDAI, CDAI; p < 0.001) and PD signals (p < 0.05). After 12 months of therapy, the ultrasonic signs of remission were found in 4 (21%) patients with clinical remission, amounting to 11% of all the patients included in the study. In a group of patients with active inflammation persisting after 48 weeks of therapy, the basal concentration of interleukin-6 (IL-6) was significantly higher than that in a group without signs of inflammation (p = 0.025). There was a trend for higher tumor necrosis factor-α (TNF-α) levels in the persistent inflammation group (p = 0.06); however, following 24 weeks, the concentration of TNF-α in the patients with persistent synovitis was significantly higher than in those without the latter (p = 0.045). The baseline level of IL-6 as a prognostic factor showed satisfactory sensitivity (71%) and specificity (67%) for a cut-off value of 46.02 pg/ml (p < 0.025). The TNF-α level of ≤51.79 pg/mg achieved after 6 months was associated with the absence of active inflammation, as evidenced by PD with 64% sensitivity and 62.5% specificity (p < 0.046). The predictive value of DAS28 following 24 weeks (3.26) was lower than that of IL-6. Thus, PD USG of hand and foot joints is a sensitive and specific method to assess RA activity. The association of the basal level of IL-6 (and TNF-α to a lesser extent) with ultrasonic changes after 48 weeks of therapy may suggest that PD USG can more accurately characterize inflammation activity than can the disease activity indices

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