ИММУНОГЕНЕТИЧЕСКИЕ АСПЕКТЫ РАННЕГО РЕВМАТОИДНОГО АРТРИТА

The study is aimed to investigate the distribution of alleles of HLA-DRB1 gene in patients with early rheumatoid arthritis and healthy individuals in Russian population, and evaluate their significance as molecular genetic markers of rheumatoid arthritis predisposition and protection. The association between alleles of HLA-DRB1 genes, antibodies to cyclic citrullinated peptides and IgM rheumatoid factor was also studied. Low and high resolution HLA-DRB1 genotyping were compared. In the cohort of patients with early rheumatoid arthritis, the alleles of HLA-DRB1 gene were found to be markers of rheumatoid arthritis protection/risk, especially in the homozygous state. They determined production of antibodies to cyclic citrullinated peptides but were not associated with rheumatoid factor IgM levels. These findings support different autoimmune mechanisms of rheumatoid arthritis pathogenesis. Изучено распределение аллелей гена HLA-DRB1 у больных ранним ревматоидным артритом и здоровых лиц контрольной группы российской популяции и оценена их значимость в качестве молекулярно-генетических маркеров предрасположенности и протекции ревматоидного артрита. Определена сила ассоциативной связи аллелей гена HLA-DRB1 с продукцией антител к циклическим цитруллинированным пептидам и ревматоидному фактору класса М. В исследовании проведено сравнение методов высоко- и низкоразрешающего генотипирования аллелей HLA-DRB1. У больных ранним ревматоидным артритом обнаружены аллели гена HLA-DRB1, являющиеся маркерами риска и протекции ревматоидного артрита, детерминирующие продукцию антител к циклическим цитруллинированным пептидам, но не ассоциированные с антителами класса M к ревматоидному фактору. Полученные данные могут свидетельствовать о различных аутоиммунных механизмах патогенеза ревматоидного артрита. 

The comparative responsiveness of Hospital Universitario Princesa Index and other composite indices for assessing rheumatoid arthritis activity

Objective To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Delta) of HUPI with Delta in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (Delta GDA-Phy). Results Delta HUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI's standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using Delta GDA-Phy as gold standard. Conclusion HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR''s

Potential uses of upadacitinib in rheumatoid arthritis and other inflammatory rheumatic diseases [ПЕРСПЕКТИВЫ ПРИМЕНЕНИЯ УПАДАЦИТИНИБА ПРИ РЕВМАТОИДНОМ АРТРИТЕ И ДРУГИХ ИММУНОВОСПАЛИТЕЛЬНЫХ РЕВМАТИЧЕСКИХ ЗАБОЛЕВАНИЯХ]

The explanation of the mechanisms underlying the pathogenesis of rheumatoid arthritis (RA), along with the development of a wide range of genetically engineered biological disease-modifying anti-rheumatic drugs (bDMARDs), is among the major achievements of medicine in the 21st century. A new direction in the pharmacotherapy of inflammatory rheumatic diseases is associated with the development of “targeted” oral anti-inflammatory drugs, which include Janus kinase (JAK) inhibitors. One representative of the class of JAK inhibitors is upadacitinib (UPA), which has been registered for the treatment of RA and is undergoing clinical studies in patients with ankylosing spondylitis, psoriatic arthritis, and other inflammatory rheumatic diseases. This review presents new data on the efficacy and safety of UPA in RA. © 2020 Ima-Press Publishing House. All rights reserved

Immunopathology and immunopharmacotherapy of coronavirus disease 2019 (covid-19): Focus on interleukin 6

The Coronavirus Disease 2019 (COVID-19) pandemic has drawn closer attention than ever before to the problems of the immunopathology of human diseases, many of which have been reflected when studying immune-mediated inflammatory rheumatic diseases (IIRDs). The hyperimmune response called a cytokine storm, the pathogenetic subtypes of which include hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and cytokine release syndrome, is among the most serious complications of IIRDs or treatment for malignant neoplasms and may be a stage of COVID-19 progression. A premium is placed to interleukin-6 (IL-6) in the spectrum of cytokines involved in the pathogenesis of the cytokine storm syndrome. The clinical introduction of monoclonal antibodies (mAbs) that inhibit the activity of this cytokine (tocilizumab, sarilumab, etc.) is one of the major advances in the treatment of IIRDs and critical conditions within the cytokine storm syndrome in COVID-19. The review discusses data on the clinical and prognostic value of IL-6 and the effectiveness of anti-IL-6 receptor and anti-IL-6 mAbs, as well as prospects for personalized therapy of the cytokine storm syndrome in COVID-19. © 2020 Ima-Press Publishing House. All rights reserved

Coronavirus disease 2019 (covid-19) and immune-mediated inflammatory rheumatic diseases: At the crossroads of thromboinflammation and autoimmunity

Inflammation and coagulation are key basic mechanism of protection against all potentially pathogenic mechanical and biological factors targeting human organism from inner and outer environment. On the other hand, uncontrolled inflammation results in hypercoagulation, inhibition of anticoagulation and alteration of mechanisms responsible for resolution of inflammation, while production of "procoagulant" mediators (thrombin, tissue factor and others), activation of platelets and of vascular endothelial cells maintains inflammation. All factors taken together serve as the basis for a pathological process called thromboinflammation or immunothrombosis. Currently thromboinflammation is considered in the broad sense as a universal pathogenetic mechanism of numerous widespread acute and chronic conditions, including immune-mediated (autoimmune) inflammatory rheumatic diseases, oftentimes complicated by severe irreversible damage to vital organs. Thromboinflammation gained specific attention during COVID-19 (coronavirus disease 2019) pandemic, caused by SARS-Cov-2 (severe acute respiratory syndrome Coronavirus-2). COVID-19 is considered currently as systemic thromboinflammation syndrome, manifesting via generalized thrombosis of arterial and venous macro- and microvasculature, termed as COVID-19-coagulopathy. The paper discusses common pathogenetic coagulopathy mechanisms in COVID-19 and immune-mediated (autoimmune) inflammatory rheumatic diseases (IMRDs), associated with overproduction of antiphospholipid antibodies, activation of the complement system, and dis-regulated synthesis of proinflammatory cytokines, etc. Delineating the autoimmune subtype of thromboinflammation, identification of genetic (i.e., genes encoding the complement system and others) and molecular-biologic biomarkers associated with higher occurrence of COVID-19-coagulopathy are the most relevant undertakings for the current practice. Gaining insights into mechanisms of thromboinflammation and converting them into potential pharmacotherapies of IMDs would facilitate and accelerate the drafting of effective therapeutic strategies for COVID-19. © 2020 Ima-Press Publishing House. All rights reserved

Coronavirus disease (COVID-19): Rheumatological Prospects/Relevance.

In December 2019, an outbreak of a novel infection under the working name 2019-nCoV was registered in Wuhan (the Hubei Province located in China's central region), which has quickly spread throughout almost the entire world and become pandemic. The World Health Organization (WHO) proposed a new name coronavirus disease (COVID-19) for this disease, whereas the International Committee on Virus Taxonomy renamed 2019-nCov as SARS-Cov-2 (Severe Acute Respiratory Syndrome Coronavirus-2). The development of the COVID-19 pandemic is not only of great social importance, but also draws the attention of a medical community to the fundamentally new clinical and fundamental problems of the immunopathology of human diseases that are yet to be formulated. The unique experience gained in rheumatology from studies of the pathogenetic mechanisms and pharmacotherapy of immune-mediated inflammatory rheumatic diseases (IMIRDs) can be of great importance for deciphering the nature of the pathological processes that underlie the severe, potentially fatal complications of COVID-19, and may assist in improving their therapy. As for prospects in patients with IMIRDs, although the development of COVID-19 in the presence of IMIRDs has not yet fortunately been described, infection with SARS-CoV-2, like other viruses, can be assumed to cause an exacerbation of the pathological process, whereas severe immune system pathology and comorbidities can worsen the course of infection. Since, according to the current concepts, it is the «hyperimmune» response, and not just the effect only of the virus itself, that underlies lung damage and deaths from COVID-19, special attention is drawn to the effects of antirheumatic therapy that includes glucocorticoids, disease-modifying anti-rheumatic drugs (DMARDs), biological agents, and targeted DMARDs, which can have a multidirectional effect on the course of COVID-19. There are significant theoretical prerequisites for the repurposing of some drugs widely used in rheumatology for the treatment of COVID-19 and its complications. Consideration is given to the prospects of studying the immunopathology of COVID-19 and to the theoretical justifications for the use of antimalarial 4-aminoquinolines, anti-cytokine monoclonal antibodies (mAbs), and Janus kinase inhibitors for the prevention of complications and for the treatment of COVID-19. © 2020 Ima-Press Publishing House. All rights reserved

Baricitinib: New pharmacotherapy options for rheumatoid arthritis and other immune-mediated inflammatory rheumatic diseases

Deciphering the mechanisms of the pathogenesis of immune-mediated inflammatory rheumatic diseases (IMIRDs) in conjunction with designing a wide range of biological agents is one of the major medical advances in the 21stcentury. A new promising area of pharmacotherapy for IMIRDs is associated with the design of the so-called targeted oral medications that primarily include Janus kinase (JAK) inhibitors. The review presents new data on the efficacy and safety of the new JAK inhibitor baricitinib in treating rheumatoid arthritis and other IMIRDs. © 2020 Ima-Press Publishing House. All rights reserved

АУТОИММУННЫЕ РЕВМАТИЧЕСКИЕ ЗАБОЛЕВАНИЯ — ПРОБЛЕМЫ ИММУНОПАТОЛОГИИ И ПЕРСОНИФИЦИРОВАННОЙ ТЕРАПИИ

By current standards autoimmunity is a complex pathological process based on a violation of tolerance and, consequently, the pathological immune response against its own tissues components (autoantigens) leading to the development of a wide range of autoimmune diseases in humans. In recent years, multiple immune disorders both acquired and / or congenital (associated with polymorphisms of genes that regulate immune response) have been transcribed. These disorders occur at the cellular and humoral levels: thymus, intestines, peripheral blood immune cells, including T and B lymphocytes, macrophages, dendritic cells, Treg-cells (Treg), components of complement system, cytokines and others. The interaction between the development of autoimmune rheumatic (ARD) and autoinflammatory diseases and syndromes is detected; a classification of immune-inflammatory diseases is designed. The article describes the results of our studies on the treatment of ARD using innovative genetically engineered biological agents and on the research of pathogenetic mechanisms and diagnostics of ARD based on immunological and molecular biological diagnostic techniques of a wide range of molecular and cellular biomarkers (autoantibodies, inflammatory acute phase proteins, cytokines, chemokines, markers of activation of the vascular endothelium, the components of the complement system, lymphocyte subpopulations, products of metabolism of bone and cartilage tissue, genetic, epigenetic, transcriptomic markers). The approaches to personalized treatment of ARD are presented.  По современным представлениям аутоиммунитет — это комплексный патологический процесс, в основе которого лежит нарушение толерантности и, как следствие, патологический иммунный ответ в отношении компонентов собственных тканей (аутоантигенов), приводящий к развитию широкого спектра аутоиммунных заболеваний человека. В последние годы были расшифрованы многообразные нарушения иммунитета, приобретенные и/или врожденные (связаны с полиморфизмом генов, регулирующих иммунный ответ), которые реализуются на клеточном и гуморальном уровне: тимус, кишечник, иммунные клетки периферической крови, включая Т и В лимфоциты, макрофаги, дендритные клетки, регуляторные Т клетки (Трег), компоненты системы комплемента, цитокины и другие. Установлена связь между развитием аутоиммунных ревматических (АРЗ) и аутовоспалительных заболеваний и синдромов, разработана классификация иммуновоспалительных заболеваний человека. В статье рассмотрены результаты собственных исследований, касающихся лечения АРЗ с использованием инновационных генно-инженерных биологических препаратов, изучения патогенетических механизмов и диагностики АРЗ на основе иммунологических и молекулярно-биологических методов исследования широкого спектра молекулярных и клеточных биомаркеров (аутоантитела, острофазовые белки воспаления, цитокины, хемокины, маркеры активации сосудистого эндотелия, компоненты системы комплемента, субпопуляции лимфоцитов, продукты метаболизма костной и хрящевой ткани, генетические, эпигенетические, транскриптомные маркеры). Также освещены подходы к персонифицированной терапии АРЗ. 

STATE OF THE SPECIALIZED RHEUMATOLOGIC ASSISTANCE FOR THE CHILDREN AND ADULTS IN THE RUSSIAN FEDERATION. THE PROJECT OF THE FEDERAL PURPOSE ORIENTED PROGRAM «RHEUMATIC DISEASES IN 2008–2012» (BASED ON THE REPORT DELIVERED AT THE PRESIDIUM SESSION OF THE R

(Voprosy sovremennoi pediatrii = Current pediatrics. 2007;6(1):6-8)</span