ФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии», г. Новосибирск, РоссияРезюме. В обзоре данных литературы и материалах собственных исследований анализируются ряд предрасполагающих и патогенетических факторов в развитии распространенной коморбидной пато-логии -диабет-ассоциированного остеоартрита (ДАОА). Поскольку у исследователей и клиницистов пока не сложилось четкого представления о ДАОА как отдельном клиническом варианте ОА, авторам не удалось найти в литературе работ, посвященных изучению роли генетических факторов в развитии именно этого варианта болезни. Особое внимание обращено на исследования, посвященные поиску перекрестных генов -кандидатов риска развития как СД 2 типа, так и ОА: PPARγ, FTO, ADIPOQ, RAGE, которые экспрессируют белки, потенциально способные участвовать в патогенезе как ОА, так и СД. Немногочисленные данные оказались противоречивы: в некоторых работах показана ас-социация перечисленных генов с развитием диабета и остеоартрита, в других исследованиях таких связей не выявлено. Рассмотрены работы, посвященные описанию клинической характеристики ОА, ассоциированного с СД. Показана патогенетическая роль хронической гипергликемии, инсулино-резистентности, конечных продуктов гликирования (advanced glycation age products, AGE) в развитии ОА и осложнений СД. Обсуждаются механизмы развития воспаления, гуморального и клеточного иммунного ответа к компонентам хряща, участие этих механизмов в прогрессии ОА. Подчеркивается сходство механизмов вялотекущего воспаления у больных ОА и сосудистых осложнений сахарного диабета. Заключается, что ДАОА не является простым механическим сочетанием двух заболеваний. ОА и СД имеют некоторые сходные генетические, патогенетические механизмы, особый фенотип болезни и нацеливают врача, ученого на новый, холистический (персонифицированный) подход к профилактике, диагностике, лечению и прогнозу этой коморбидной патологии. Рассматриваются возможности фармакотерапии ДАОА, учитывающей ключевую характеристику коморбидных забо-леваний -эмерджентность (возникающие свойства). Предполагается, что изучение универсальных сетевых взаимодействий, происходящих на геномном, молекулярном, клеточном уровнях, которые приводят к поражению различных органов-мишеней, позволит успешно использовать подход «сете-вой фармакологии» в терапии коморбидных заболеваний. Приводятся примеры успешного использо-вания такого лечения при некоторых полипатиях (фармакологический агонист PPARα фенофибрат, ингибитор ГМГ-КоА редуктазы симвастатин при ОА, РА и псориазе). Обсуждается реальность этих подходов в терапии ДАОА. В частности, приводится пример использования в пилотных исследовани-ях донатора метильной группы адеметионина. 630047, Россия, г. Новосибирск, ул. Ядринцевская, 14. Тел.: 8 (923) 107-51-00. Факс: 8 (383) 228-25-47.
Резюме. Остеоартрит (ОА) является гетерогенным заболеванием, один из возможных субтипов ОА -диабет-ассоциированный ОА. В настоящее время клинические и иммунологические характери-стики ОА, связанного с диабетом, не изучены. Для оценки фенотипа диабет-ассоциированного ОА, связи его клинических проявлений с уровнем цитокинов ПК, обследовано 78 больных с генерализо-ванным ОА: 52 больных опытной группы (82,6% женщины), у которых клиническим проявлениям ОА не менее года предшествовал СД 2 и 26 больных ОА (84,6% женщины) без сахарного диабета. Установлено, что клинические проявления ОА в сочетании с СД отличаются от таковых у больных ОА и характеризуются большей массой тела, более выраженным уровнем боли в суставах, увеличением продолжительности утренней скованности, большим уровнем снижения функции опорных суставов и кисти, качества жизни и большей тяжестью болезни. Тяжелые проявления ОА более свойственны у больных с плохо контролируемым СД, вынужденных принимать препараты инсулина. В сыворотке крови больных ОА в сочетании с СД, в отличие от больных ОА выявлено повышение уровня провос-палительных (IL-6, IL-18) и снижение противоспалительных цитокинов (IL-10, адипонектин), и этот дисбаланс свидетельствует о более выраженном системном воспалении у пациентов первой группы. Содержание IL-6 в сыворотке крови коррелирует с рядом функциональных показателей тяжести ОА. Заключается, что ОА в сочетании с СД является особым субтипом ОА, требующим дальнейшего изучения иммунопатогенеза и разработки новых подходов к лечению. Ключевые слова: сахарный диабет 2 типа, остеоартрит, цитокины, коморбидность, воспаление CLINICAL AND IMMUNOLOGICAL CHARACTERISTICS OF DIABETES-ASSOCIATED OSTEOARTHRITISShirinsky I.V., Kalinovskaya N.Yu., Shirinsky V.S. Research Institute of Clinical immunology, Siberian Branch, Russian Academy of Medical Sciences, Novosibirsk, Russian FederationAbstract. Osteoarthritis (OA) has been shown to be a heterogeneous disease. Diabetes mellitus (DM)-associated represents a special OA subtype. Its clinical and immunological characteristics are poorly understood. To assess immune phenotype of the diabetes-associated OA and appropriate relationship between its clinical manifestations and cytokine concentrations in peripheral blood, we examined 78 patients with generalized OA including 52 patients in experimental group (82.6% females) who exhibited clinical manifestations of OA Адрес для переписки: Ширинский Иван Валерьевич ФГБУ «НИИ клинической иммунологии» СО РАМН 630047, Россия, г. Новосибирск, ул. Залесского, 6. Тел.: 8 (383) 228-25-47. Факс: 8 (383) 228-25-47.
In this review we analyze literature data concerning participation of synovial inflammation, subchondral bone, humoral and cellular immune responses towards various cartilage autoantigens in the initiation and progression of primary osteoarthritis (OA). The vast majority of studies showed that the synovial inaflammation in OA is less pronounced than in RA but is more pronounced than in healthy people. In OA synovial tissue, macrophages and T-cells predominate in the inflammatory infiltrate. Some authors detected mast cells in the OA synovium in quantities higher than in healthy control and significantly higher than in RA patients. Most of researchers found many cytokines related to innate and adaptive immune cells in the OA synovial tissue, while in some studies the cells producing those cytokines were not identified. Among the cytokines there were both pro-inflammatory and anti-inflammatory ones: IL-1b, TNFα, IFNγ, IL-4, IL-2, IL-6, IL-8, IL-10, IL-17, IL-18. In addition, some authors detected IL-5, IL-13, IL-19, IL-21, IL-26, IL-32, and TGFb. A role of adaptive immune response in OA is supported by the presence of autoantibodies against antigen determinants of collagens type II, IX, XI, aggrecan, fibronectin fragments, in the synovial tissue, synovium fluid, and peripheral blood serum. The research data clearly support a role of chronic inflammation and changes in innate and adaptive immune response in the pathogenesis of OA thus justifying the change of the disease name from “osteoarthrosis” to “osteoarthritis”. This novel understanding of OA pathogenesis is paramount as it provides a rationale for modern anti-inflammatory treatments and discovery of new therapeutic targets. We discuss the results of studies evaluating efficacy and safety of some types of anti-inflammatory treatment of OA. Until now, treatment of OA directed on inflammation control was not successful. Thus, clinical trials of anti-TNFα anti-IL-1b strategies for the treatment of OA did not show clinically significant improvement in spite of multiple studies demonstrating elevated concentrations of TNFα and IL-1bin synovial fluid and subchondral bone in OA thus suggesting the role of these cytokines in the OA pathogenesis. On the other side, treatment with IL-1 inhibitor diacerein was found to be effective which can be explained by pleiotropic effects of this drug. It should be stressed out that in order to increase the efficacy of anti-inflammatory treatments of OA they should be initiated at early disease stages, thus necessitating the use of new informative biormarkers of early OA.
The review article considers the data from literature that concern polymorbidity aspects, its interrelations with ageing of immune system and lo-grade immune ageing, mechanisms of genesis, approaches to its prevention and treatment. Evolution of “comorbidity” and “polymorbidity” terms is traced, an updated definition of polymorbidity is proposed. The world-wide incidence of polymorbidity is increased and now it reaches 23-25% in general population, and up to 98%, in elderly people (> 65 years old). The risk factors of polymorbidity are considered, like as its social burden due to high costs for healthcare, high mortality rates, excessive treatment provided by multidisciplinary specialists. We present evidence for common molecular and cellular mechanisms involved in ageing and polymorbidity, being unified by the term “inflammaging” which represents a low-grade chronic systemic inflammation associated with ageing. The data are presented that concern the “inflammaging” development with involvement of ageing cells from innate and adaptive immunity systems, different pro and anti-inflammatory mediators, lifelong antigenic load. The data are analyzed concerning functional and structural changes in the inborn and adaptive immune system in ageing, role of these changes in “inflammaging” persistence and development of polymorbid conditions. There are complex interactions shown between the bodily senescence and immune ageing, with similar underlying mechanisms in some cases, however, being quite different in other instances. With age, upon existing risk factors, the changed adaptive immunity in most people is not able to full-scale coping with chronic antigenic load, thus increasing the risk of diseases. Moreover, in many elderly people these changes are compensated by steady activation of the innate immunity cells. It is noted that the aging events and development of disease (polymorbidity) cannot be considered distinct entities, since they can interact, being, however, basically different in their nature. In future, one should concentrate our efforts on elucidation of molecular and cellular mechanisms of these interactions, solution of the tasks oriented for development of such interventions that could be able to reduce harmful consequences of ageing and to use useful effects for health maintenance and reaching maximal longevity.
Objective: to study the efficacy and safety of rheumatoid arthritis (RA) treatment with monoclonal antibodies to interleukin 6 receptors (IL6R) – sarilumab (SAR) in combination with methotrexate (MT).Subjects and methods. The study included adult patients with moderate or severe RA and inadequate effect of MT monotherapy. Patients were randomized in a 1:1:1 ratio to subgroups receiving SAR (at doses of 150 or 200 mg) or placebo (PL) every 2 weeks in combination with a weekly intake of MT for 52 weeks. The primary endpoints of the study included the achievement of ACR20 after 24 weeks, the change of HAQ-DI after 16 weeks and assessment of radiological progression of joint destruction (modified total Sharp score mTSS) after 52 weeks.Results and discussion. In general, the initial characteristics of patients were similar in all groups. A statistically significant improvement of all three primary endpoints was found in the groups of patients treated with SAR 150 and 200 mg compared to the group of PL. ACR20 response after 24 weeks was achieved in 53.6% (p<0.0005), 65.9 and 19.6% of patients respectively (p<0.0001), the average change in HAQ-DI after 16 weeks was 20.53; 20.55 and 20.29 respectively (p<0.0001); the average change in mTSS after 52 weeks was 0.49; 0.11 and 2.30, respectively (p<0.0001).Conclusion. Both doses of SAR (150 and 200 mg every 2 weeks) in combination with MT demonstrated sustained clinical efficacy in patients with RA, which was confirmed by a significant improvement in symptomatic, functional and radiographic outcomes. SAR therapy was generally well tolerated. The adverse events observed in this study were consistent with the effects of the IL6 blockade.
Here we review literature data on properties of a member of nuclear hormone receptors - peroxisome proliferator-activated receptor-α. It was shown that PPARα was expressed on different cells including dendritic cells, macrophages, B- and T-cells. We discuss structure of natural and synthetic ligands of PPARa, molecular and cellular mechanisms of PPARa regulation of lipid and carbohydrate cellular metabolism. PPARa activity in hepatocytes results in decrease of intracellular concentrations of lipid acids. This leads to reduction of VLDL cholesterol, increase in HDL-cholesterol and decrease in triglycerides in plasma of patients taking PPARα agonists. Modulation of PPARa activity may change multiple biological effects of glucocorticoids (GCS) and insulin resistance. It is assumed that PPARα agonists reduce side effects of GCS and at the same time enhance their anti-inflammatory activity due to transrepression of NF-kB. We analyzed the results of several randomized studies, meta-analyses devoted to assessment of efficacy and safety of PPARa agonist fenofibrate in patients with type 2 diabetes mellitus with high risk of micro- and macrovascular events. The studies showed good safety profile of monotherapy with fibrates as well as of their combinations with statins, ezetimibe. Fibrates reduced not only cardiovascular events but also overall mortality. We present the data on the role of PPARa in control of glucose and lipid metabolism in subpopulations of innate and adaptive immunity cells. The data show that glucose and lipid metabolism play an important role in the fate of cells of innate and adaptive immunity. The metabolic state of lymphocytes has dynamic nature and depends on their functional activity. Transition from dormant cells with relatively low metabolism rate to activated and proliferating cells is accompanied with increase of metabolic demands. This transition is supported with the switch from oxidative metabolism to anaerobic glycolysis (Warburg effect) after antigen recognition by T-cells and B-cells. It was shown that granulocytes, dendritic cells and M1 macrophages were dependent on glucose metabolism during their activation while M2 macrophages were dependent on fatty acids oxidation. In contrast with lymphocytes, activated myeloid cells do not proliferate well but still have increased glycolysis which is necessary for their effector function. It is stressed that modulation of immune cells metabolism via PPARα gives new opportunities to modulate intensity and duration of immune responses in chronic diseases. We analyze studies performed on animal models of some chronic diseases, human patients with rheumatoid arthritis and different phenotypes of osteoarthritis. Most of the studies showed clinical efficacy and pleiotropic effects of PPARα agonists: antiinflammatory, immunomodulating and lipid modulating, primarily reduction of triglycerides and increase in HDL-C. The presented literature data suggest efficacy of PPARα agonists against individual components of polypathies. This could reduce risk of polypharmacy and reduce direct treatment costs. It is not unlikely that the use of PPARα agonists in a patient with multimorbidity could prevent acquiring a new disease. These are merely suggestions and much effort and time is required to perform large-scale randomized controlled studies evaluating new indications for the use of PPARa agonists.
Forty women with gonarthrosis were included in this study. The main group consisted of 19 patients having osteoarthritis (OA) with metabolic syndrome (MS), the control group consisted of 21 patients with OA but without MS. It was found that metabolic phenotype of gonarthrosis, i.e. OA with concomitant MS, was different from OA without MS in terms of pain measured with visual analogue scale (VAS) (65 mm in the main group vs 47 mm in control group, р = 0.001) and other OA symptoms in accordance with Knee Osteoarthritis Outcome Scale (KOOS) (43.2 points in the main group vs 76.1 points in the control group, р = 0.001). These main distinguishing features were associated with low quality of life measured with non-specific questionnaire Short Form -36 (SF-36) (30 points in the main group and 40 points in the control) and clinically significant signs of depression, detected with Patient Health Questionnaire-9 (PHQ-9) (12 points in the main group and 7 points in the control group). The metabolic phenotype of gonarthrosis was characterized with laboratory features of low-grade systemic inflammation as evidenced by increased CRP (11.4 mg/ml in the main group vs 3.2 mg/ml in the control group, р = 0.03), IL-6 (2.6 pg/ml in the main group vs 0.7 pg/ml in the control group, р = 0.001), IL-18 (196.6 pg/ml in the main group vs 61.4 pg/ml in the control group, р = 0.001) in the peripheral blood serum, as well as increase in antibodies against Col2 (27.1 ng/ml in the main vs 5.5 ng/ml in the control group, р = 0.01) , and dyslipidaemia — increase in LDL-cholesterol (5.5 mmol/l in the main group vs 5.9 mmol/l in the control group, р = 0.032) and triglycerides (2.026 mmol/l in the main group and 1.36 mmol/l in the control gropu, р = 0.02). In conclusion, MS-associated OA phenotype occurs due to pathogenetic similarities between OA and MS (syntropy) based on systemic low grade inflammation. This OA phenotype is not well studied and needs further research to develop new treatments targeting these two comorbid disorders as a single disease.
Treatment of osteoarthritis (OA) patients with comorbidities can be challenging due to adverse events and non-sufficient efficacy of modern drugs. A safe and effective alternative could be the methods of traditional medicine and their combinations. The aim of this study was to evaluate efficacy and safety of combination of curcuma-based parapharmaceutical preparation and acupuncture in metabolic phenotype of OA (MPOA). The trial design was pilot open-label “before – after” study with the duration of 12 weeks. The patients with MPOA received parapharmaceutical preparation Epigenorm Antivir in a daily dose of 1000 mg and underwent 15-20 sessions of classical acupuncture. We enrolled twenty three women with metabolic syndrome (MS), clinical and radiographic signs of gonarthrosis, mean age 66.5 years, mean body mass index 34.5. At the end of treatment there was a decrease in pain levels according to visual analogue scale (VAS) (before 65 (12.7), after 24.6 (21.0), р=0.001), WOMAC pain scale (before 210.6 (102.2), after 103 (80.8), p = 0.014), KOOS (before 47.8 (12.1), after 66.7 (16.2), р = 0.001). The treatment resulted in statistically significant improvement of daily and social activities, role functioning, and quality of life. The results were clinically significant as evidenced by the moderate (Cohen d > 0.5) and large (Cohen d > 0.8) effect sizes of most outcome changes in accordance with the Cohen classification. The clinical improvement was accompanied by the decrease in MS components – LDL cholesterol (before 3.26 (0.26) mmol/l, after 2.43 (0.2) mmol/l, р = 0.001), triglycerides (before 2.02 (0.16) mmol/l, after 1.31 (0.1) mmol/l, р = 0.005). The treatment resulted in the reduction of systemic inflammation as evidenced by the decrease in the concentrations of TNFα (before 15.9 (1.2) pg/ml, after 12.4 (0.8), р = 0.002), histamine (before 1.6 (0.2) ng/ml, after 0.7 (0.2) pg/ml, р = 0.034), IL-18 (before 208.8 (32.6 ) pg/ml, after 160.0 (26.0) pg/ml, р = 0.002) and CRP (before 6.05 (1.3) mg/l, after 3.2 (0.7) mg/l, р = 0.022). At the same time there was an increase of concentration of IL-10 (before 1.5 (0.7) pg/ml, after 3.8 (1.2), р = 0,006) and adiponectin (before 34.0 (5.6) pg/ml, after 40.0 (6.9), р = 0.034). The treatment was well tolerated, no serious adverse events were registered. The pleiotropic actions of combination treatment occured probably due to synergistic effects of herbal therapies and acupunctures. The results provide a rationale for larger scale, randomized controlled double-blind clinical trials.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.