Prophylaxis of Acute Arthritis at Initiation of Urate-Lowering Therapy in Gout Patients

During the first months after the initiation of urate-lowering therapy in gout patients, the risk of exacerbation of arthritis considerably rises, which often results in discontinuation of the prescribed therapy by patients. The main way to avoid this risk is preventive prescription of colchicine, NSAIDs or glucocorticoids. Such prophylaxis of acute arthritis has been specified in a large number of the latest editions of various national and international guidelines; however, this tactics is rarely used in practice. The chapter includes the most significant studies on this problem

Autoimmunity in rheumatology: A review

Autoimmunity and autoinflammation, co-potentiating pathological processes, are considered within the "immune-inflammatory" continuum (continuity with a variety of elements), reflecting the close relationship between the innate and acquired immune responses. Autoimmunity is the leading pathogenetic mechanism for a specific type of human chronic inflammatory disorders – autoimmune diseases, affecting more than 10% of people in the general population. Advances in molecular biology, pharmacogenetics, and bioinformatics provided the background for individualizing therapy for systemic autoimmune rheumatic diseases within personalized medicine. Studying the immunopathogenesis mechanisms, improving diagnostics, interpreting the molecular taxonomy, and developing approaches to the prevention and personalized therapy of systemic autoimmune rheumatic diseases are the priority issues of modern medicine

Новые направления фармакотерапии ревматических заболеваний – ингибиция интерлейкина 6 и интерлейкина 17

Significant progress related particular to the use of interleukin (IL)-6 and IL17 inhibitors has been made in the pharmacotherapy of rheumatic diseases. IL-6 is a cytokine that has a wide range of biological activity and affects different types of cells. There is evidence for the important role of IL-6 hyperproduction not only in rheumatoid arthritis (RA), but also in other immune inflammatory rheumatic diseases (systemic lupus erythematosus (SLE), scleroderma systematica, idiopathic inflammatory myopathies, giant cell arteritis, etc.). IL-6 inhibition primarily with humanized monoclonal antibodies against IL-6 receptors (tocilizumab – TCZ)) is considered as one of the promising areas of pharmacotherapy for these diseases. The successful results of TCZ use have created pre requisites for the design of other medicaments that can form a novel class of IL-6 inhibitors, genetically engineered biological agents, in the future. There is another new area in the treatment of immune inflammatory rheumatic diseases, which is the inhibition of the cytokine IL17A that provides interaction between innate and acquired immunity and is synthesized by a wide range of immunocompetent cells, the socalled Th17 ones in particular. IL-17A is implicated in the immunopathogenesis of a broad spectrum of immune inflammatory diseases, including RA, psoriasis, psoriatic arthritis, inflammatory bowel diseases, SLE, allergic diseases, transplantation immunity, obesity, carcinogenesis, etc. Elevated IL-17A concentrations correlate with the activity and severity of a pathological process. The pathogenetic effects of IL-17 in RA may be associated with its involvement in the development of synovial inflammation and joint destruction. The therapeutic efficiency of inhibition of Th17 cells and IL-17A synthesis in autoimmune diseases was first indirectly demonstrated in psoriasis. This providedthe basis for the elaboration of therapeutic approaches associated with the direct inhibition of IL-17 effects in these patients. Thus, the use of IL-6 inhibitors (primarily TCZ) and, probably, IL-17 will make significant progress in the treatment of not only RA, but other severe potentially deadly immune inflammatory rheumatic diseases in the future.В фармакотерапии ревматических заболеваний достигнут значительный прогресс, связанный, в частности, с использованием ингибиторов интерлейкина (ИЛ) 6 и ИЛ17. ИЛ6 – цитокин, который имеет широкий спектр биологической активности и действует на различные типы клеток. Получены данные о важной роли гиперпродукции ИЛ6 не только при ревматоидном артрите (РА), но и при других иммуновоспалительных ревматических заболеваниях (системной красной волчанке – СКВ, системной склеродермии, идиопатических воспалительных миопатиях, гигантоклеточном артериите и др.). Ингибиция ИЛ6, в первую очередь с использованием гуманизированных моноклональных антител к рецепторам ИЛ6 (тоцилизумаб – ТЦЗ), рассматривается как одно из наиболее перспективных направлений фармакотерапии этих заболеваний. Успешные результатыприменения ТЦЗ создали предпосылки для разработки других лекарственных средств, которые в перспективе могут сформировать новый классгенно-инженерных биологических препаратов – ингибиторы ИЛ6. Еще одно новое направление в лечении иммуновоспалительных ревматических заболеваний – ингибиция цитокина ИЛ17А, который обеспечиваетвзаимодействие между врожденным и приобретенным иммунитетом, синтезируется широким спектром иммунокомпетентных клеток, в частности так называемыми Th17-клетками. ИЛ17А задействован в иммунопатогенезе широкого спектра иммуновоспалительных заболеваний, включая РА, псориаз, псориатический артрит, воспалительные заболевания кишечника, СКВ, а также аллергических заболеваний, трансплантационного иммунитета, ожирения, канцерогенеза и др. Увеличение концентрации ИЛ17А коррелирует с активностью и тяжестью патологическогопроцесса. Патогенетические эффекты ИЛ17 при РА могут быть связаны с его участием в развитии синовиального воспаления и деструкции суставной ткани.Впервые терапевтическая эффективность ингибиции Th17-клеток и синтеза ИЛ17А при аутоиммунных заболеваниях была косвенно продемонстрирована при псориазе. Это послужило основанием для разработки терапевтических подходов, связанных с прямой ингибицией эффектов ИЛ17 у таких пациентов.Таким образом, применение ингибиторов ИЛ6 (в первую очередь ТЦЗ), а также, вероятно, ИЛ17 в перспективе позволит достигнуть существенного прогресса в лечении не только РА, но и других тяжелых потенциально смертельных иммуновоспалительных ревматических заболеваний

INTERLEUKIN-17 IS A NEW TARGET FOR ANTI-CYTOKINE THERAPY OF IMMUNE INFLAMMATORY RHEUMATIC DISEASES

As of now, there have been notable advances in treating immune inflammatory rheumatic diseases, which are associated with the interpretation of basic pathogenetic mechanisms of their development. The most well studied therapeutic targets are tumor necrosis factor-α, interleukin (IL)-6 and IL-1; inhibition of these cytokines with genetically engineered biological agents is not always clinically effective and rarely gives rise to remission. The new promising treatment of rheumatoid arthritis (RA) and other inflammatory arthritides is linked to the inhibition of IL-17A, a proinflammatory cytokine, involved in the development of inflammation and in the destruction of bone tissue. The paper summarizes new evidence for the prospects of using anti-interleukin-17 monoclonal antibodies to treat RA

Effectiveness of two different doses of rituximab for the treatment of rheumatoid arthritis in an international cohort : data from the CERERRA collaboration

Background: The approved dose of rituximab (RTX) in rheumatoid arthritis is 1000 mg x 2, but some data have suggested similar clinical efficacy with 500 mg x 2. The purpose of this study was to compare the effectiveness of the regular and low doses given as first treatment course. Methods: Twelve European registries participating in the CERERRA collaboration (The European Collaborative Registries for the Evaluation of Rituximab in Rheumatoid Arthritis) submitted anonymized datasets with demographic, efficacy and treatment data for patients who had started RTX. Treatment effectiveness was assessed by DAS28 reductions and EULAR responses after 6 months. Results: Data on RTX dose were available for 2,873 patients, of whom 2,625 (91.4 %) and 248 (8.6 %) received 1000 mg x 2 and 500 mg x 2, respectively. Patients treated with 500 mg x 2 were significantly older, had longer disease duration, higher number of prior DMARDs, but lower number of prior biologics and lower baseline DAS28 than those treated with 1000 mg x 2. Fewer patients in the low-dose group received concomitant DMARDs but more frequently received concomitant corticosteroids. Both doses led to significant clinical improvements at 6 months. DAS28 reductions at 6 months were comparable in the 2 dose regimens [mean DeltaDAS28 +/- SD -2.0 +/- 1.3 (high dose) vs. -1.7 +/- 1.4 (low dose), p = 0.23 adjusted for baseline differences]. Similar percentages of patients achieved EULAR good response in the two dose groups, 18.4 % vs. 17.3 %, respectively (p = 0.36). Conclusions: In this large observational cohort initial treatment with RTX at 500 mg x 2 and 1000 mg x 2 led to comparable clinical outcomes at 6 months.Peer reviewe

Oral abstracts 3: RA Treatment and outcomesO13. Validation of jadas in all subtypes of juvenile idiopathic arthritis in a clinical setting

Background: Juvenile Arthritis Disease Activity Score (JADAS) is a 4 variable composite disease activity (DA) score for JIA (including active 10, 27 or 71 joint count (AJC), physician global (PGA), parent/child global (PGE) and ESR). The validity of JADAS for all ILAR subtypes in the routine clinical setting is unknown. We investigated the construct validity of JADAS in the clinical setting in all subtypes of JIA through application to a prospective inception cohort of UK children presenting with new onset inflammatory arthritis. Methods: JADAS 10, 27 and 71 were determined for all children in the Childhood Arthritis Prospective Study (CAPS) with complete data available at baseline. Correlation of JADAS 10, 27 and 71 with single DA markers was determined for all subtypes. All correlations were calculated using Spearman's rank statistic. Results: 262/1238 visits had sufficient data for calculation of JADAS (1028 (83%) AJC, 744 (60%) PGA, 843 (68%) PGE and 459 (37%) ESR). Median age at disease onset was 6.0 years (IQR 2.6-10.4) and 64% were female. Correlation between JADAS 10, 27 and 71 approached 1 for all subtypes. Median JADAS 71 was 5.3 (IQR 2.2-10.1) with a significant difference between median JADAS scores between subtypes (p < 0.01). Correlation of JADAS 71 with each single marker of DA was moderate to high in the total cohort (see Table 1). Overall, correlation with AJC, PGA and PGE was moderate to high and correlation with ESR, limited JC, parental pain and CHAQ was low to moderate in the individual subtypes. Correlation coefficients in the extended oligoarticular, rheumatoid factor negative and enthesitis related subtypes were interpreted with caution in view of low numbers. Conclusions: This study adds to the body of evidence supporting the construct validity of JADAS. JADAS correlates with other measures of DA in all ILAR subtypes in the routine clinical setting. Given the high frequency of missing ESR data, it would be useful to assess the validity of JADAS without inclusion of the ESR. Disclosure statement: All authors have declared no conflicts of interest. Table 1Spearman's correlation between JADAS 71 and single markers DA by ILAR subtype ILAR Subtype Systemic onset JIA Persistent oligo JIA Extended oligo JIA Rheumatoid factor neg JIA Rheumatoid factor pos JIA Enthesitis related JIA Psoriatic JIA Undifferentiated JIA Unknown subtype Total cohort Number of children 23 111 12 57 7 9 19 7 17 262 AJC 0.54 0.67 0.53 0.75 0.53 0.34 0.59 0.81 0.37 0.59 PGA 0.63 0.69 0.25 0.73 0.14 0.05 0.50 0.83 0.56 0.64 PGE 0.51 0.68 0.83 0.61 0.41 0.69 0.71 0.9 0.48 0.61 ESR 0.28 0.31 0.35 0.4 0.6 0.85 0.43 0.7 0.5 0.53 Limited 71 JC 0.29 0.51 0.23 0.37 0.14 -0.12 0.4 0.81 0.45 0.41 Parental pain 0.23 0.62 0.03 0.57 0.41 0.69 0.7 0.79 0.42 0.53 Childhood health assessment questionnaire 0.25 0.57 -0.07 0.36 -0.47 0.84 0.37 0.8 0.66 0.4

Coronavirus disease-2019 (COVID-19): Value of IL-6 inhibitors

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