Коронавирусная болезнь-2019 (COVID-19): значение ингибиторов IL-6

The coronavirus disease 2019 (COVID-19) pandemic has drawn attention to new clinical and fundamental issues in the immunopathology of human diseases. Since in COVID-19 it is the ‘‘hyperimmune’’ response, called cytokine storm syndrome, which forms the basis of the pathogenesis of acute respiratory distress syndrome (ARDS) and multiorgan dysfunction in COVID-19, special attention is drawn to the possibility of “repurposing” (drug repurposing) of some widely used for treatment immune-mediated inflammatory rheumatic diseases (IMIRDs) anti-inflammatory drugs, including glucocorticoids (GC), disease-modified anti-rheumatic drugs (DMARDs), biologic agents and ‘‘targeted’’ DMARDs. In the spectrum of cytokines involved in the pathogenesis of cytokine storm syndrome in IMIRDs and COVID-19, great importance is attached to the pro-inflammatory cytokine, interleukin IL-6. The development and introduction into clinical practice of monoclonal antibodies (mAbs) that inhibit the activity of IL-6 are among the major advances in the treatment of IMIRDs, and in recent years, critical conditions within the framework of the cytokine storm syndrome, including in COVID-19. The review discusses the materials of numerous studies devoted to the problems of the efficacy and safety of mAbs to the IL-6 receptor (tocilizumab) and other mAbs that inhibit the activity of this cytokine in COVID-19. Despite the effectiveness of inhibiting IL-6 in patients with severe COVID-19, many theoretical and clinical problems of immunopathology and pharmacotherapy of this disease require further study.Пандемия коронавирусной болезни-2019 (COVID-19) привлекла внимание к новым клиническим и фундаментальным проблемам иммунопатологии заболеваний человека. Поскольку при COVID-19 именно гипериммунный ответ, получивший наименование синдром «цитокинового шторма», составляет основу патогенеза острого респираторного дистресс-синдрома и мультиорганной дисфункции при COVID-19. При этом особенно привлекательной является возможность репозиционирования (drug repurposing) некоторых широкоприменяемых для лечения иммуновоспалительных ревматических заболеваний (ИВРЗ) противовоспалительных лекарственных препаратов, включая глюкокортикостероиды, базисные противовоспалительные препараты, генно-инженерные биологические препараты и таргетные базисные противовоспалительные препараты. В спектре цитокинов, принимающих участие в патогенезе синдрома «цитокинового шторма» при ИВРЗ и COVID-19, большое значение придается провоспалительному цитокину интерлейкину (IL)-6. Разработка и внедрение в клиническую практику моноклональных антител (мАТ), ингибирующих активность IL-6, относится к числу крупных достижений в лечении ИВРЗ, а в последние годы – критических состояний в рамках синдрома «цитокинового шторма», в т. ч. при COVID-19. В обзоре обсуждаются материалы многочисленных исследований, посвященных проблемам эффективности и безопасности мАТ к рецептору IL-6 (тоцилизумаб) и других мАТ, ингибирующих активность этого цитокина при COVID-19. Несмотря на эффективность ингибирования IL-6 у пациентов с тяжелым течением COVID-19, требуется дальнейшее изучение многих теоретических и клинических проблем иммунопатологии и фармакотерапии этого заболевания

NEW GUIDELINES FOR THE MANAGEMENT OF RHEUMATOID ARTHRITIS (EULAR, 2013): THE PLACE OF GLUCOCORTICOIDS

Despite major advances in the management of rheumatoid arthritis (RA), whicare associated with the development of new methods for its early diagnosis, the clinical introduction of a wide range of innovative medications and particularly the improvement of a strategy for their use, glucocorticoids (GC) still remain the most important component of pharmacotherapy for this disease in real clinical practice. This publication that is a continuation of a series of papers devoted to the discussion of the main points of the 2013 European League against Rheumatism (EULAR) guidelines for the treatment of early RA, deals with the place of GC. An analysis of available data suggests that GC should be reserved for patients showing a high activity of the inflammatory process and having factors associated with a poor prognosis, but also, in the absence of risk factors for adverse events (AE), of course, contraindications to GC therapy. Throughout the use of GC, their AE should be meticulously monitored in compliance with the EULAR guidelines. Itis anticipated that the wider use of combined therapy with methotrexate and a GC in earlyRA will be able to improve its prognosis in at least some patients and to cause a substantial decrease in the burden of disease, by reducing the risk of disability and the needs for expensive biological agents and joint replacement. All this confirms that it is relevant to include the proposition for using GC into the 2014 Guidelines for the management of rheumatoid arthritis of the All-Russian public organization “Association of Rheumatologists of Russia”

Новые возможности фармакотерапии системной красной волчанки: место белимумаба

Systemic lupus erythematosus (SLE) is a multifactorial disease caused by complex interactions between the genetic and environmental factors underlying various innate and adaptive immunity disorders, including cytokine hyperproduction, abnormal B cell activation, impaired intracellular T-cell signaling, and defective apoptotic and necrotic cell clearance. A broad spectrum of genetic disorders associated with susceptibility to the disease and/or its definite variants has been identified. Our knowledge concerning the mechanisms of polyclonal B cell activation in SLE has advanced substantially. Various defects in the T cells regulating a B cell immune response have been detected. The development of genetic, epigenomic, transcriptomic, and proteomic technologies could identify a group of pathogenetically relevant cytokines, including BLyS (the B-lymphocyte stimulator is the most important component of cytokine-mediated regulation of B cell function, proliferation, and differentiation), interleukin (IL) 6, 17, 18, type 1 interferon, and tumor necrosis factor-α, which are involved in the development of visceral inflammation and damage.Large-scale clinical trials of different medications, primarily biological agents (BA), were conducted in patients with SLE. Rituximab (RTM) is the first BA to be used to treat this disease. Despite its official registration for the therapy of SLE, RTM is included in the EULAR, ACR, and Russia's Association of Rheumatologists guidelines for its treatment. Belimumab, a fully human recombinant IgG1λmonoclonal antibody, specially designed to treat SLE, prevents the interaction of pBLyS with the receptors of autoreactive transitional and naive B cells, giving rise to the suppression of B cell hyperresponsiveness, autoantibody synthesis in particular. In addition, BLyS block may cause decreased survival of B cells in the germinal centers of lymphoid organs, differentiation of memory B cells into autoantibody-producing cells, and synthesis of proinflammatory cytokines (IL-21, IL-17, and others) that play an important role in the immunopathogenesis of SLE. Despite its moderate efficacy, belimumab will be able to improve pharmacotherapy for this disease.Системная красная волчанка (СКВ) – мультифакторное заболевание, обусловленное сложным взаимодействием генетических и внешнесредовых факторов, лежащих в основе многообразных нарушений врожденного и приобретенного иммунитета, в том числе гиперпродукции цитокинов, патологической активации В-клеток, нарушения внутриклеточной сигнализации Т-клеток, дефектов клиренса клеток, подвернутых апоптозу и нетозу. Идентифицирован широкий спектр генетических нарушений, ассоциирующихся с «чувствительностью» к развитию заболевания и/или определенными вариантами его течения. Существенно расшились знания о механизмах поликлональной В-клеточной активации при СКВ. Выявлены разнообразные дефекты Т-клеток, регулирующих В-клеточный иммунный ответ.Разработка генетических, эпигеномных, транскриптомных и протеомных технологий позволила определить группу патогенетически значимых цитокинов, в том числе BLyS (B-lymphocyte stimulator – важнейший компонент цитокиновой регуляции функции, пролиферации и дифференцировки В-клеток), интерлейкин (ИЛ) 6, 17, 18, интерферон типа 1, фактор некроза опухоли (ФНО) α, которые участвуют в развитии воспаления и повреждения внутренних органов.Проведены широкомасштабные клинические исследования различных лекарственных средств, в первую очередь генно-инженерных биологических препаратов (ГИБП) у больных СКВ. Первым ГИБП, который начали применять для лечения СКВ, был ритуксимаб (РТМ). Несмотря на отсутствие официальной регистрации для лечения СКВ, РТМ включен в рекомендации EULAR, ACR и Ассоциации ревматологов России по лечению СКВ. Специально разработанный для лечения СКВ белимумаб – полностью человеческие рекомбинантные моноклональные антитела (IgG1 λ) – предотвращает взаимодействие рBLyS с клеточными рецепторами аутореактивных «переходных» (transitional) и наивных В-клеток, что приводит к подавлению В-клеточной гиперреактивности, в частности синтеза аутоантител. Кроме того, блокада BLyS может вызывать снижение выживаемости В-клеток в ростковых центрах лимфоидных органов, дифференцировку В-клеток памяти в аутоантитело-продуцирующие клетки и синтез «провоспалительных» цитокинов (ИЛ21, ИЛ17 и др.), которые играют важную роль в иммунопатогенезе СКВ. Несмотря на умеренную эффективность белимумаба при СКВ, появление препарата позволит усовершенствовать фармакотерапию этого заболевания

Прогресс ревматологии в начале XXI века

Rheumatoid arthritis (RA), juvenile arthritis, spondyloarthritis, including psoriatic arthritis, systemic lupus erythematosus (SLE), and other systemic connective tissue diseases, are the most severe chronic immunoinflammatory rheumatic diseases (IIRDs) that affect as high as 10% of the population. Substantial progress has been made in the treatment of IIRDs in the 21st century. The current Treat to Target (T2T) strategy for RA is to achieve remission as soon as possible. The main treatment goal is to improve quality of life, by controlling the symptoms of the disease, by preventing joint destruction and dysfunction, and by maintaining social possibilities. The most important way to achieve this goal is to inhibit inflammation and to evaluate the efficiency of treatment, by using the standardized activity indices and by choosing the appropriate treatment option. The widespread use of biological agents in combination with standard disease-modifying antirheumatic drugs could substantially enhance therapeutic effectiveness. A new class of medicaments (chemically synthesized small molecular weight agents) to treat RA has appeared. The point of their application is tyrosine kinases, primarily Janus kinase (JAK). The new era in the treatment of SLE and other IIRDs is associated with the design of the new class of drugs Р BLyS inhibitors. In the coming years, the main lines of researches by Russian rheumatologists will be to elaborate a strategy to prevent IIRDs; to introduce innovative methods for their early diagnosis and treatment (biological agents, JAK inhibitors, and other cell signaling molecules) and for the prediction of the outcomes of the most severe forms of IIRD; to realize the concept of personified medicine (to investigate the prognostic biomarkers of the efficiency and safety of targeted therapy), to reduce the risk of infectious complications, cardiovascular diseases, cancer, osteoporotic fractures, and other comorbidities.Ревматоидный артрит (РА), ювенильные артриты, спондилоартриты, включая псориатический артрит, системная красная волчанка (СКВ) и другие системные заболевания соединительной ткани, – наиболее тяжелые хронические иммуновоспалительные ревматические заболевания (ИВРЗ), которыми страдает до 10% популяции. В XXI в. достигнут значительный прогресс в лечении ИВЗР. Основой современной стратегии лечения РА – «Лечение до достижения цели» (Treat to Target – T2T) – является максимально быстрое достижение ремиссии заболевания. Основная задача лечения – улучшение качества жизни пациентов путем контроля симптомов заболевания, предотвращение деструкции и нарушения функции суставов, сохранение социальных возможностей. Важнейший путь для достижения этой цели – подавление воспаления; оценка эффективности лечения с помощью стандартизированных индексов активности заболевания и соответствующего подбора терапии. Широкое использование при РА генно-инженерных биологических препаратов (ГИБП) в комбинации со стандартными базисными противовоспалительными препаратами (БПВП) позволило существенно повысить эффективность терапии. Появился новый класс препаратов для лечения РА – низкомолекулярные химически синтезированные вещества (small molecules). Их точка приложения – тирозинкиназы, в первую очередь Янус-киназы (JAK). Прогресс в лечении СКВ и других ИВРЗ связан с созданием нового класса лекарственных препаратов – ингибиторов BLyS. Основными направлениями научных исследований российской ревматологии в ближайшие годы будут: разработка стратегии профилактики ИВРЗ; внедрение инновационных методов ранней диагностики и лечения (ГИБП, ингибиторы JAK-киназ и других сигнальных молекул), а также прогнозирования исходов наиболее тяжелых форм ИВЗР; реализация концепции персонифицированной медицины (изучение прогностических биомаркеров эффективности и безопасности «таргетной» терапии), снижение риска инфекционных осложнений, кардиоваскулярной, онкологической патологии, остеопоретических переломов и других коморбидных заболеваний

MODERN IDEA ON THE PATHOGENESIS OF SPONDYLOARTHRITIS: MOLECULAR MECHANISMS

As of now, impaired immune homeostasis of the intestinal mucosa in genetically predisposed individuals is considered to be one of the major components in the pathogenesis of spondyloarthritis (SpA), which leads to systemic chronic inflammation. The results of recent studies may suggest that the interleukin-23/interleukin-17 (IL-23/IL-17) axis plays a leading role in the development of these diseases. The multifactorial components of the pathogenesis of SpA are characterized by not only the hyperproduction of IL-23, but also by the change in cell target susceptibility to this cytokine with aconcurrent increase in their number, resulting in the chronic autoinflammatory process that occurs via a wide spectrum of clinical manifestations of different types of Sp

AUTOIMMUNE RHEUMATIC DISEASES: RESULTS AND PROSPECTS FOR RESEARCHES

According to the present-day views, autoimmunity is a complex pathological process, the essence of which is intolerance and hence a pathological immune response to intrinsic tissue components (autoantigens), which underlies the pathogenesis of a broad spectrum of human autoimmune diseases. Recently, diverse immune disorders underlying autoimmune rheumatic diseases (ARD) and syndromes have been revealed; an association has been found between the development of ARD and autoinflammatory diseases and syndromes; a classification of human immunoinflammatory diseases has been elaborated. The paper considers the results of the authors’ investigations of ARD treatment with innovative biologics, the pathogenetic mechanisms and diagnosis of ARD, by conducting immunological and molecular biological studies of a wide range of molecular and cellular biomarkers (autoantibodies, acute phase proteins, cytokines, chemokines, vascular endothelial activation markers, complement system components, lymphocyte subpopulations, bone and cartilage tissue metabolic products, genetic, epigenetic, transcriptomic markers), and approaches to personalized treatment of ARD

THE CLINICAL SIGNIFICANCE OF MATRIX METALLOPROTEINASES IN RHEUMATOID ARTHRITIS PATIENTS (REVIEW OF THE LITERATURE AND OUR OWN DATA)

Matrix metalloproteinases (MMPs) are a group of over 20 proteolytic enzymes responsible for cleavage of protein components of the extracellular matrix. Three types of MMPs play an important role in the development of joint damage in patients with rheumatoid arthritis (RA): collagenases (MMP1, 8 and 13), stromelysins (MMP3), and gelatinases (MMP9). MMP3 is considered to be one of the key mediators of joint damage. Increased serum level of MMP is not specific for RA and may be registered in other rheumatic diseases (osteoarthritis, psoriatic arthritis, gout, ankylosing spondylitis, systemic lupus erythematosus); however, monitoring of the level of MMP is of particular clinical importance in patients with RA. MMP3 serum level may be a useful marker of disease activity. Several studies have shown a correlation of MMP3 concentration with clinical and laboratorial parameters of inflammatory activity (ESR and C-reactive protein – CRP) in RA patients. The elevated level of MMP3 is associated with radiological changes in joints and can also be a predictor of severe destructive lesions in RA patients. Evaluation of the MMP3 level can also be useful for monitoring the therapy effectiveness using both standard disease-modifying antirheumatic drugs (DMARDs) and genetically engineered biological drugs (GEBD). Thus, evaluation of MMP3 concentration is useful for assessing disease activity and efficacy of treatment with DMARDs and GEBD, as well as for predicting the severity of destructive changes in joints

Prospects for the use of monoclonal antibodies to interleukin 23 Gusеlkumab in psoriatic arthritis: New data

Among the pathophysiological mechanisms of immune-mediated inflammatory diseases (IMIDs), specific attention has been paid to the abnormal activation of Th17 type immune response related to the dysregulated synthesis of cytokines forming the interleukin (IL)-23 and IL-17 axis. IL-23 blockade is an innovative approach to the treatment of psoriasis and psoriatic arthritis (PsA). Much of the interest has focused on guselkumab (GUS) (TREMFYA, Janssen, Johnson & Johnson, USA), a fully human IgG λ monoclonal antibody (mAb) targeting the p19 IL-23 subunit and the first-in-class treatment approved for patients with psoriasis and PsA. In patients with psoriasis, GUS is at least as effective as other biologic therapies for PsA and is superior to ustekinumab, an anti-IL-12/IL-23 mAb, and secukinumab, an anti-IL-17 mAb. Compared with TNF-α inhibitors, GUS therapy is less likely to cause infections and does not increase the risk of the reactivation of latent TB infection. The new GRAPPA guidelines (2021) recommend GUS (and other IL-23 inhibitors) for patients with PsA resistant to conventional disease-modifying antirheumatic drugs (DMARDs), who have peripheral arthritis, enthesitis, dactylitis, psoriatic skin and nail lesions. The paper discusses new data on the efficacy of GUS in patients resistant to TNF-α inhibitors, its benefits in patients with axial PsA, and safety during the COVID-19 pandemic

Genetically engineered biological agents in therapy for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototype for chronic autoimmune disease. Its prevalence is 20 to 70 cases per 100,000 women and varies by race and ethnicity. Despite considerable progress in traditional therapy, many problems associated with the management of these patients need to be immediately solved: thus, 50-80% are found to have activity signs and/or frequent exacerbations and about 30% of the patients have to stop work; Class IV lupus nephritis increases the risk of terminalrenal failure. In the past 20 years great progress has been made in studying the pathogenesis of SLE: biological targets to affect drugs have been sought and fundamentally new therapeutic goals defined. Belimumab is the first genetically biological agent specially designed to treat SLE, which is rightly regarded as one of the most important achievements of rheumatology in the past 50 years