Situational analysis of socio-cultural interaction of states under conditions of globalization

The present article considers the possibilities of the paradigm of socio-cultural interaction when analyzing international relations. Traditional activity approaches in explaining this interaction are critically assessed, and the main situations of interstate interactions that have a socio-cultural importance are analyzed. The offered problematisation when studying global strategies of interstate relations in terms of socio-cultural interaction makes it possible to consider desirable strategies and scenarios for improving intercultural communication and international cooperation. Possible prospects on changing the basic benchmarks of the globalization processes based on socio-cultural interaction for its further humanization are outlined. The revealed mechanisms of the dynamics of socio-cultural interactions when moving from one situation of interaction to another, as well as the role of the cultural reality formed for this purpose and overcoming the one-sidedness of economism in international relations can provoke the researchers’ interest. The offered analysis of the situations of socio-cultural interaction enables the authors of the article to clarify some positive opportunities of the globalization in the overall civilization development and intercultural dialogue of all countries of the world community. The results given in the article in relation to studying the main reasons of the discrimination in interstate relations and offers on overcoming it by using the spiritual and moral potential of the world culture are also of great importance.peer-reviewe

Результаты молекулярно-генетического скрининга мутаций генов NLRP3, TNFRSF1A, MVK у пациентов с аутовоспалительными заболеваниями и системным ювенильным артритом

Autoinflammatory diseases (AIDs) are being intensively studied. Molecular genetic testing of patients is of great importance for the diagnosis of AIDs since the basis for its development is pathological mutations that cause innate (antigen-nonspecific) immunity system disorders and the development of inflammation. This also applies to patients with systemic juvenile arthritis (SJA) that has been recently assigned to a group of AIDs due to the great similarity of symptoms. In this connection, the assumption that monogenic AIDs mask SJA in a number of patients was well founded. More than 25 genes, mutations in which lead to AIDs, are known; the NLRP3, TNFRSF1A, and MVK genes are most common and well investigated. These genes cause major monogenic AIDs, such as cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulinemia D/deficit mevalonate kinase syndrome (HIDS).Objective: to identify patients with monogenic AIDs among those with fever, arthralgias, and other manifestations of systemic inflammatory response, including among those with SJA, through molecular genetic testing.Patients and methods. In 2012–2016, molecular genetic testing for mutations in the NLRP3, MVK, and TNFRSF1A genes was carried out within the framework of screening in 184 patients (94 women and 90 men). The investigation enrolled 117 patients with suspected AIDs (Group 1) and 67 patients with SJA (Group 2). The selection criteria were periodic or persistent fever, clinical manifestations of systemic inflammatory response (skin rashes, arthralgias/arthritis, lymphadenopathy, hepatolienal syndrome, serositis, etc.), acute-phase markers when excluding infectious, oncohematologic, and autoimmune causes. SJA was diagnosed based on the ILAR criteria (2001). The patients' age ranged from 6 months to 60 years (mean age, 9.0 years [5; 15]), disease duration, 2 months to 54 years (mean duration, 3.0 [1.0; 8.5])). To identify familial aggregation, genetic tests were also carried out in 18 relatives of the patients with genetically verified AIDs. Molecular genetic analysis was performed in the Laboratory of Hereditary Metabolic Diseases, Research Center of Medical Genetics, Moscow.Results. 15 variants of pathogenic mutations in the studied genes were identified in 43 (23.4%) patients: 31 (16.8%) patients with those in NLRP3, 10 (5.4%) in TNFRSF1A (in a heterozygous state), and 2 (1.1%) in MVK (in a compound heterozygous state). In the AID group, the mutations were detected in 31 (26.5%) patients: 24 (20.5%) in NLRP3, 1 (0.9%) in MVK, and 6 (5.1%) in TNFRSF1A. In the SJA group, the mutations were present in 12 (17.9%) patients: 7 (10.4%) in NLRP3, 1 (1.5%) in MVK, and 4 (5.9%) in TNFRSF1A. The most common mutations in the NLRP3 gene were substitution-missense c. 1049C>T (p.T350M) in 7 (25.9%) patients and low-penetrance mutation c. 2113C>A (p. Q705K) in 13 (28.3%). Examinations established the genetic diagnoses of CAPS in 19 (10.3%) patients, TRAPS in 9 (4.9%), and HIDS in 2 (1.1%). In Group 1, CAPS was identified in 17 (14.5%) patients, of whom 15 had Muckle-Wells syndrome (MWS) and 2 had CINCA/NOMID (Chronic infantile neurologic, cutaneous articular syndrome (CINCA)/Neonatal onset multisystem inflammatory disorder (NOMID); TRAPS and HIDS were present in 6 (5.1%) and 1 (0.9%) patients, respectively. In Group 2, there was CAPS (MWS) in 2 (2.9%) patients, TRAPS in 3 (4.5%), and HIDS in 1 (1.5%). Eleven of the 18 relatives of the patients were ascertained to have mutations and 7 were diagnosed as having AIDs (CAPS in 4, TRAPS in 3).Conclusion. About one-quarter of the patients who have an inflammatory phenotype, including the manifestations of SJA, suffer from monogenic AIDs. Half of them received therapy with the interleukin-1 inhibitor canakinumab, which had a pronounced positive effect. Interpretation of the diagnostic value of low-penetrance mutations is hampered and requires an individual approach. The diagnosis of AIDs should be established in patients having no mutations with great caution, in this case, there is a need for clinical and laboratory criteria for the disease and a thorough assessment of the data of medical history of the patient, and his/her family in particular. The decision to assign these patients to receive lifetime expensive targeted therapy should be well justified.Аутовоспалительные заболевания (АВЗ) интенсивно изучаются. Большое значение для диагностики АВЗ имеет молекулярно-генетическое тестирование пациентов, поскольку основой развития АВЗ являются патологические мутации, обусловливающие нарушения в системе врожденного (антиген-неспецифического) иммунитета и развитие воспаления. Это касается и пациентов с системным ювенильным артритом (СЮА), который в последние годы отнесен к группе АВЗ ввиду большой схожести симптоматики. В связи с этим вполне обоснованным стало предположение, что у ряда пациентов под маской СЮА скрываются моногенные АВЗ. Известно более 25 генов, мутации в которых приводят к развитию АВЗ, наиболее распространенными и хорошо изученными являются гены NLRP3, TNFRSF1A и MVK. Эти гены вызывают развитие основных моногенных АВЗ: криопирин-ассоциированных периодических синдромов (Сryopyrin-аssociated рeriodic syndromes, CAPS), периодического синдрома, ассоциированного с мутацией гена рецептора фактора некроза опухоли (TNF-receptor-associated periodic syndrome, TRAPS) и синдрома гипериммуноглобулинемии Д/ дефицита мевалонат-киназы (Hyper-immunoglobulinemia D-syndrome, HIDS).Цель исследования – с помощью молекулярно-генетического тестирования выявить пациентов с моногенными АВЗ среди больных с лихорадкой, артралгиями и другими проявлениями системного воспалительного ответа, в том числе среди пациентов с СЮА.Пациенты и методы. В 2012–2016 гг. в рамках скринингового обследования 184 больным (94 женского, 90 мужского пола) было выполнено молекулярно-генетическое тестирование на мутации в генах NLRP3, MVK и TNFRSF1A. В исследование включено 117 пациентов с подозрением на АВЗ (1-я группа) и 67 больных СЮА (2-я группа). Критериями включения служили наличие периодической или персистирующей лихорадки, клинических проявлений системной воспалительной реакции (кожные высыпания, артралгии/артрит, лимфаденопатия, гепатолиенальный синдром, серозит и др.), острофазовых маркеров при исключении инфекционных, онкогематологических и аутоиммунных причин. Диагноз СЮА устанавливали на основании критериев ILAR (2001). Возраст больных варьировал от 6 мес до 60 лет (М – 9,0 лет [5; 15]), длительность заболевания – от 2 мес до 54 лет (М – 3,0 года [1,0; 8,5]). Для выявления семейной агрегации генетические тесты были выполнены также 18 родственникам пациентов с генетически подтвержденными АВЗ. Молекулярно-генетический анализ осуществляли в лаборатории наследственных болезней обмена веществ ФГБНУ «Медико-генетический научный центр», Москва.Результаты. У 43 (23,4%) обследованных выявлены 15 вариантов патогенных мутаций в изучаемых генах: у 31 (16,8%) больного – в NLRP3, у 10 (5,4%) – в TNFRSF1A (в гетерозиготном состоянии) и у 2 (1,1%) – в MVK (в компаунд-гетерозиготном состоянии). В группе АВЗ мутации обнаружены у 31 (26,5%) пациента: у 24 (20,5%) – в NLRP3, у 1 (0,9%) – в MVK, у 6 (5,1%) – в TNFRSF1A. В группе CЮА мутации имелись у 12 (17,9%) больных: у 7 (10,4%) – в NLRP3, у 1 (1,5%) – в MVK и у 4 (5,9%) – в TNFRSF1A. Наиболее частыми мутациями в гене NLRP3 были миссенс-замена c. 1049C>T (p.T350M), выявленная у 7 (25,9%) пациентов, а также мутация низкой пенетрантности с. 2113C>A (р.Q705K), обнаруженная у 13 (28,3%) пациентов. В результате обследования были установлены генетические диагнозы: CAPS – у 19 (10,3%) пациентов, TRAPS – у 9 (4,9%), HIDS – у 2 (1,1%). В 1-й группе: CAPS определен у 17 (14,5%) больных, из них у 15 имелся синдром Макла–Уэллса (Muckle–Wells syndromе, MWS) и у 2 – CINCA/NOMID (Сhronic infantile neurologic, cutaneus articular syndrome – CINCA; Neonatal onset multisystem inflammatory disorder – NOMID); TRAPS – у 6 (5,1%), HIDS – у 1 (0,9%); во 2-й группе: CAPS (MWS) установлен у 2 (2,9%) больных, TRAPS – у 3 (4,5%), HIDS – у 1 (1,5%). Из 18 родственников больных у 11 выявлены мутации и у 7 диагностированы АВЗ (у 4 – CAPS, у 3 – TRAPS).Выводы. Среди пациентов, имеющих воспалительный фенотип, в том числе проявления СЮА, почти четверть страдают моногенными АВЗ. Половине из них проведена терапия ингибитором интерлейкина 1 канакинумабом с выраженным положительным эффектом. Интерпретация диагностической значимости низкопенетрантных мутаций затруднена и требует индивидуального подхода. У негативных по мутациям пациентов диагноз АВЗ нужно устанавливать с большой осторожностью, при этом необходимы наличие клинико-лабораторных критериев заболевания, тщательная оценка данных анамнеза, особенно семейного. Решение о назначении таким больным дорогостоящей пожизненной таргетной терапии должно быть хорошо обоснованным

AUTOINFLAMMATORY DISEASES IN RHEUMATOLOGY: RUSSIAN EXPERIENCE

<p>Autoinflammatory diseases (AIDs) are characterized by periodic, sometimes self-limiting attacks that appear as fever and clinical symptoms resembling rheumatic ones, in the absence of autoimmune or infectious diseases. The group of AIDs encompasses a broad spectrum of nosological entities; some of them have been recently dealt with by rheumatologists.</p><p><strong>Objective:</strong> to define the spectrum of AIDs in the practice of a pediatric rheumatologist from the results of visits to the Russian Federal Rheumatology Center.</p><p><strong>Subjects and methods.</strong> The investigation enrolled patients who had visited the V.A. Nasonova Research Institute of Rheumatology in 2007 to 2015 for fever and other signs of a systemic inflammatory process in order to specify their diagnosis and to rule out infections, blood cancer, and other diseases. All underwent conventional rheumatologic examination, HLA Class A typing, and molecular genetic testing.</p><p><strong>Results and discussion.</strong> 101 patients aged 6.5 months to 60 years with AIDs were identified over 9 years and diagnosed as having the following diseases. Familial Mediterranean fever (FMF) was detected in 17 patients (the female to male (M/F) ratio was 6:11); Behсet's disease (BD) in 25 children (M/F, 14:11), cryopyrin-associated periodic syndromes (CAPS) in 17 patients, including Muckle–Wells syndrome in 13 (M/F, 4:9); chronic infantile neurologic cutaneous articular and neonatal onset multisystem inflammatory disease (CINCA/NOMID) syndrome in 4 (M/F, 3:1), periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome in 17 (M/F, 10:7), hyper-IgD syndrome/mevalonate kinase deficiency syndrome in 3 (M/F, 0:3), tumor necrosis factor receptor periodic syndrome (TRAPS) in 7 (M/F, 4:3), undifferentiated AID in 14, and Blau syndrome in one patient. The patients with BD were rather ethnically diverse: among them, there were representatives of North Caucasian peoples, Tatars, Uzbeks, Moldavians, and others; there were 7 ethnic Russians. There was a preponderance of Armenians among FMF patients (15/17). Ethnic Russians were predominant among the patients with other nosological entities. HLA-B5 antigen was found in 9 (36%) patients with BD. Molecular genetic analysis confirmed the diagnosis in virtually all the patients with monogenic AIDs.</p><p><strong>Conclusion.</strong> The most common AIDs in our practice were BD, FMF, CAPS, and PFAPA. The patients with CAPS were closest in clinical and laboratory presentations to those with rheumatic disease, particular to those diagnosed with systemic juvenile arthritis and this disease should be kept in mind in differential diagnosis. Our practical experience indicated that targeted therapy with interleukin 1 inhibitors was effective in CAPS patients. This treatment is able to substantially improve an initial poor prognosis.</p

Results of molecular genetic screening of mutations in the NLRP3, TNFRSF1A, and MVK genes in patients with autoinflammatory diseases and systemic juvenile arthritis

Autoinflammatory diseases (AIDs) are being intensively studied. Molecular genetic testing of patients is of great importance for the diagnosis of AIDs since the basis for its development is pathological mutations that cause innate (antigen-nonspecific) immunity system disorders and the development of inflammation. This also applies to patients with systemic juvenile arthritis (SJA) that has been recently assigned to a group of AIDs due to the great similarity of symptoms. In this connection, the assumption that monogenic AIDs mask SJA in a number of patients was well founded. More than 25 genes, mutations in which lead to AIDs, are known; the NLRP3, TNFRSF1A, and MVK genes are most common and well investigated. These genes cause major monogenic AIDs, such as cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulinemia D/deficit mevalonate kinase syndrome (HIDS).Objective: to identify patients with monogenic AIDs among those with fever, arthralgias, and other manifestations of systemic inflammatory response, including among those with SJA, through molecular genetic testing.Patients and methods. In 2012–2016, molecular genetic testing for mutations in the NLRP3, MVK, and TNFRSF1A genes was carried out within the framework of screening in 184 patients (94 women and 90 men). The investigation enrolled 117 patients with suspected AIDs (Group 1) and 67 patients with SJA (Group 2). The selection criteria were periodic or persistent fever, clinical manifestations of systemic inflammatory response (skin rashes, arthralgias/arthritis, lymphadenopathy, hepatolienal syndrome, serositis, etc.), acute-phase markers when excluding infectious, oncohematologic, and autoimmune causes. SJA was diagnosed based on the ILAR criteria (2001). The patients' age ranged from 6 months to 60 years (mean age, 9.0 years [5; 15]), disease duration, 2 months to 54 years (mean duration, 3.0 [1.0; 8.5])). To identify familial aggregation, genetic tests were also carried out in 18 relatives of the patients with genetically verified AIDs. Molecular genetic analysis was performed in the Laboratory of Hereditary Metabolic Diseases, Research Center of Medical Genetics, Moscow.Results. 15 variants of pathogenic mutations in the studied genes were identified in 43 (23.4%) patients: 31 (16.8%) patients with those in NLRP3, 10 (5.4%) in TNFRSF1A (in a heterozygous state), and 2 (1.1%) in MVK (in a compound heterozygous state). In the AID group, the mutations were detected in 31 (26.5%) patients: 24 (20.5%) in NLRP3, 1 (0.9%) in MVK, and 6 (5.1%) in TNFRSF1A. In the SJA group, the mutations were present in 12 (17.9%) patients: 7 (10.4%) in NLRP3, 1 (1.5%) in MVK, and 4 (5.9%) in TNFRSF1A. The most common mutations in the NLRP3 gene were substitution-missense c. 1049C&gt;T (p.T350M) in 7 (25.9%) patients and low-penetrance mutation c. 2113C&gt;A (p. Q705K) in 13 (28.3%). Examinations established the genetic diagnoses of CAPS in 19 (10.3%) patients, TRAPS in 9 (4.9%), and HIDS in 2 (1.1%). In Group 1, CAPS was identified in 17 (14.5%) patients, of whom 15 had Muckle-Wells syndrome (MWS) and 2 had CINCA/NOMID (Chronic infantile neurologic, cutaneous articular syndrome (CINCA)/Neonatal onset multisystem inflammatory disorder (NOMID); TRAPS and HIDS were present in 6 (5.1%) and 1 (0.9%) patients, respectively. In Group 2, there was CAPS (MWS) in 2 (2.9%) patients, TRAPS in 3 (4.5%), and HIDS in 1 (1.5%). Eleven of the 18 relatives of the patients were ascertained to have mutations and 7 were diagnosed as having AIDs (CAPS in 4, TRAPS in 3).Conclusion. About one-quarter of the patients who have an inflammatory phenotype, including the manifestations of SJA, suffer from monogenic AIDs. Half of them received therapy with the interleukin-1 inhibitor canakinumab, which had a pronounced positive effect. Interpretation of the diagnostic value of low-penetrance mutations is hampered and requires an individual approach. The diagnosis of AIDs should be established in patients having no mutations with great caution, in this case, there is a need for clinical and laboratory criteria for the disease and a thorough assessment of the data of medical history of the patient, and his/her family in particular. The decision to assign these patients to receive lifetime expensive targeted therapy should be well justified

Low-penetrance R92Q (p.Arg121Gln) mutation in the <i>TNFRSF1A</i> gene: the significance and variants of phenotypes. Successful experience with the interleukin-1 inhibitor canakinumab in a female patient, who is a carrier of R92Q mutation with a severe TRAPS phenotype

The paper is devoted to the assessment of the R92Q (p.Arg121Gln) mutation/polymorphism in the TNFRSF1A gene associated with the monogenic autoinflammatory disease – Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS). It gives data on the frequency of this gene in the general population, which is 1.3% and significantly exceeds the incidence of TRAPS. The authors describe the variants of phenotypes associated with its mutation from asymptomatic carriage to the development of a severe systemic autoinflammatory state with persistent febrile fever and a significant increase in the level of acute-phase inflammatory markers that do not respond to standard antirheumatic therapy. They present a clinical case of the high efficiency of the anti-interleukin 1β monoclonal antibody canakinumab in a female patient with a severe TRAPS phenotype, who had the R92Q mutation and hormonal dependence. Canakinumab therapy led to complete relief from all manifestations of the disease and to discontinuation of glucocorticoids. The authors conclude that the decision to prescribe therapy with biological agents should be made on the basis of the clinical severity of the disease rather than a variant of the mutation that caused it