EFFECTIVENESS OF EDUCATIONAL PROGRAMS ON EARLY DIAGNOSIS OF ANKYLOSING SPONDYLITIS FOR PRIMARY CARE PHYSICIANS IN KAZAN

The diagnosis of ankylosing spondylitis (AS) in the real-life practice is delayed for 7–8 years on average. Educational programs for primary care physicians may promote the disease diagnosis. Objective. To analyze the effectiveness of the educational programs for the early diagnosis of AS for primary contact physicians in the real-life clinical practice in Kazan. Material and methods. The development of the educational programs and determination of their effectiveness com- prised three stages: 1) determination of the level of knowledge and problems in the diagnosis and treatment of AS among primary care physicians and neurologists; 2) development of educational programs suitable to be used in the real-life clinical practice; 3) analysis of the effectiveness of implementing the programs according to the reports on work of the City Rheumatology Center in 2009–2011. Results. After running the courses, the number of patients with AS at the Kazan City Rheumatology Center increased almost twofold, from 378 in 2009 to 683 in 2011; the period from the onset of the disease to diagnosis was simultane- ously reduced from 8.4 to 3.5 years. Conclusion. The educational programs for primary care physicians and neurologists in Kazan have promoted shorten- ing of the AS diagnosis time

Efficacy and tolerability of adalimumab (humira) in patients with active rheumatoid arthritis

Objective: to evaluate the efficacy and tolerability of adalimumab alone and in combination with basic anti-inflammatory drugs (BAIDs) in patients with rheumatoid arthritis (RA), by taking into account the specific features of the course of the disease. Subjects and methods. The study enrolled 30 patients with a verified diagnosis of RA, its high activity by DAS 28, and ineffective previous therapy with standard BAIDs. At the beginning of the study, 20 (66.7%) patients continued taking BAIDs. According to therapy, the patients were divided into 3 groups: 1) 10 (33.3%) patients received subcutaneous adalimumab injections only; 2) 12 (40%) took adalimumab+methotrexate (MT); 3) 8 (26.7%) had adalimumab+leflunomide. The patient groups were matched for age, the duration and activity of RA (by DAS 28), its X-ray stage and seropositivity. Nine (37.5%) patients took oral glucocorticoids (GCs) and 25 (83.3%) received non-steroidal anti-inflammatory drugs (NSAIDs). Two (8.3%) patients had previously been prescribed biological therapies. Adalimumab was subcutaneously injected every 2 weeks for 24 weeks. The quantitative parameters of articular syndrome and blood and urine biochemical and clinical analyses were used to evaluate therapeutic effectiveness. The effect of therapy was evaluated by the ACR and EULAR (DAS 28) criteria. The efficiency of therapy was evaluated 12 and 24 weeks after therapy. Results. The clinical and laboratory effect of adalimumab was noted in 29 (96.7%) of the 30 patients. All the assessed parameters of articular syndrome became significantly lower (p<0.001) by week 12 of therapy and to a greater extent by week 24. Evaluation of the efficiency of adalimumab therapy by the ACR criteria showed that following 12-week therapy, the parameters were decreased by 20% in 87% of the patients and 50% in 16.7%; after 24 weeks, 23.3, 70 and 96.7% achieved very good (ACR 70), good (ACR 50), and satisfactory (ACR 20) effects. Estimation of the time course of changes in the disease activity index (DAS 28) revealed that adalimumab significantly reduced disease activity. Therapeutic effectiveness was also shown as reduced needs for NSAIDs and GCs. Positive clinical and laboratory changes during adalimumab+ MT combination therapy were also demonstrated to be significantly higher than those during adalimumab monotherapy or adalimumab + leflunomide combination therapy. Conclusion. Adalimumab is an effective disease-modifying biological agent. Its benefits may include the rapid development (on days 4-5 on average) and long retention (for 6 months or more) of an effect, a good safety profile (adverse reactions occurred only in 16.7% of the patients), and easiness-to-use

Эффективность и переносимость адалимумаба (Хумира) у пациентов с активным ревматоидным артритом

Objective: to evaluate the efficacy and tolerability of adalimumab alone and in combination with basic anti-inflammatory drugs (BAIDs) in patients with rheumatoid arthritis (RA), by taking into account the specific features of the course of the disease. Subjects and methods. The study enrolled 30 patients with a verified diagnosis of RA, its high activity by DAS 28, and ineffective previous therapy with standard BAIDs. At the beginning of the study, 20 (66.7%) patients continued taking BAIDs. According to therapy, the patients were divided into 3 groups: 1) 10 (33.3%) patients received subcutaneous adalimumab injections only; 2) 12 (40%) took adalimumab+methotrexate (MT); 3) 8 (26.7%) had adalimumab+leflunomide. The patient groups were matched for age, the duration and activity of RA (by DAS 28), its X-ray stage and seropositivity. Nine (37.5%) patients took oral glucocorticoids (GCs) and 25 (83.3%) received non-steroidal anti-inflammatory drugs (NSAIDs). Two (8.3%) patients had previously been prescribed biological therapies. Adalimumab was subcutaneously injected every 2 weeks for 24 weeks. The quantitative parameters of articular syndrome and blood and urine biochemical and clinical analyses were used to evaluate therapeutic effectiveness. The effect of therapy was evaluated by the ACR and EULAR (DAS 28) criteria. The efficiency of therapy was evaluated 12 and 24 weeks after therapy. Results. The clinical and laboratory effect of adalimumab was noted in 29 (96.7%) of the 30 patients. All the assessed parameters of articular syndrome became significantly lower (p<0.001) by week 12 of therapy and to a greater extent by week 24. Evaluation of the efficiency of adalimumab therapy by the ACR criteria showed that following 12-week therapy, the parameters were decreased by 20% in 87% of the patients and 50% in 16.7%; after 24 weeks, 23.3, 70 and 96.7% achieved very good (ACR 70), good (ACR 50), and satisfactory (ACR 20) effects. Estimation of the time course of changes in the disease activity index (DAS 28) revealed that adalimumab significantly reduced disease activity. Therapeutic effectiveness was also shown as reduced needs for NSAIDs and GCs. Positive clinical and laboratory changes during adalimumab+ MT combination therapy were also demonstrated to be significantly higher than those during adalimumab monotherapy or adalimumab + leflunomide combination therapy. Conclusion. Adalimumab is an effective disease-modifying biological agent. Its benefits may include the rapid development (on days 4-5 on average) and long retention (for 6 months or more) of an effect, a good safety profile (adverse reactions occurred only in 16.7% of the patients), and easiness-to-use.Цель наблюдения - оценка эффективности и переносимости адалимумаба у больных РА как при монотерапии, так и в комбина- ции с базисными противовоспалительными препаратами (БПВП) с учетом особенностей течения заболевания. Материал и методы. В наблюдение было включено 30 больных с достоверным диагнозом РА и высокой активностью болезни по DAS 28 и неэффективностью предшествующей терапии стандартными БПВП. К моменту начала наблюдения продолжали принимать БПВП 20 (66,7%) пациентов. В соответствии с терапией пациенты были разделены на три группы: только подкожные инъекции адалимумаба по- лучали 10 (33,3%) больных, адалимумаб+метотрексат (МТ) - 12 (40%) и адалимумаб+лефлуномид - 8 (26,7%). Группы пациентов бы- ли сопоставимы по возрасту, длительности, активности РА (по DAS 28), его рентгенологической стадии и серопозитивности. Пероральные глюкокортикоиды (ГК) получали 9 (37,5%) больных, нестероидные противовоспалительные препараты (НПВП) - 25 (83,3%). Терапию биологическими агентами в прошлом назначали 2 (8,3%) пациентам. Адалимумаб вводили подкожно каждые 2 нед в течение 24 нед. Для оценки эффективности лечения использовали количественные параметры суставного синдрома, биохимические, клинические анализы крови и мочи. Эффект терапии оценивали по критериям ACR и EULAR (DAS 28). Оценку эффективности проводили через 12 и 24 нед терапии. Результаты. Клинико-лабораторный эффект адалимумаба отмечен у 29 (96,7%) из 30 больных. Все оцениваемые параметры сус- тавного синдрома достоверно (p<0,001) уменьшались к 12-й неделе и еще в большей степени - к 24-й неделе терапии. Оценка эф- фективности лечения адалимумабом по критериям ACR показала, что через 12 нед терапии уменьшение параметров на 20% от- мечалось у 87% больных, на 50% - у 16,7%; через 24 нед ответ на терапию зарегистрирован у 96,7% больных (ACR 20), 70% (ACR 50) и 23,3% (ACR 70). При оценке динамики индекса активности болезни (DAS 28) выявлено, что адалимумаб достоверно снижал активность заболева- ния. Эффективность терапии проявлялась также в снижении потребности в НПВП и ГК. Положительная динамика клинико-ла- бораторных показателей на фоне комбинированной терапии адалимумабом+МТ была достоверно выше, чем при монотерапии ада- лимумабом или использовании комбинации адалимумаб + лефлуномид. Заключение. Адалимумаб - эффективный болезнь-модифицирующий биологический препарат. К его преимуществам можно отне- сти быстрое развитие (в среднем на 4-5-й день) и длительное сохранение (6 мес и более) эффекта, хороший профиль безопасности (побочные явления возникли лишь у 16,7 больных), удобство введения

Метастазирование аденокарциномы желудка в тело и шейку матки. Клинический случай

Comprehensive approach and a highly qualified morphological analysis are important conditions for timely diagnosis and development of tactics of pathogenetic treatment of cancer patients. This clinical case demonstrates a multimodal approach to the differential diagnosis of metastatic cancer. Due to oncological alertness, the clinical data, qualitative morphological study and close cooperation of all participants in a multidisciplinary group a metastasis of the gastric signet-ring cell carcinoma was diagnosed in the cervix, allowing to optimize treatment of the patient.Комплексный подход и качественный морфологический анализ являются важными условиями своевременной постановки диагноза и выработки тактики патогенетического лечения онкологических больных. Данный клинический случай демонстрирует мультимодальный подход к дифференциальной диагностике метастатического опухолевого процесса. Благодаря онкологической настороженности, клиническим данным, качественному морфологическому исследованию и тесному взаимодействию всех участников мультидисциплинарной команды был диагностирован метастаз перстневидно-клеточного рака желудка в шейку матки, что позволило оптимизировать лечение больной

Density‐ and size‐dependent mortality in fish early life stages

The importance of survival and growth variations early in life for population dynamics depends on the degrees of compensatory density dependence and size dependence in survival at later life stages. Quantifying density‐ and size‐dependent mortality at different juvenile stages is therefore important to understand and potentially predict the recruitment to the population. We applied a statistical state‐space modelling approach to analyse time series of abundance and mean body size of larval and juvenile fish. The focus was to identify the importance of abundance and body size for growth and survival through successive larval and juvenile age intervals, and to quantify how the dynamics propagate through the early life to influence recruitment. We thus identified both relevant ages and mechanisms (i.e. density dependence and size dependence in survival and growth) linking recruitment variability to early life dynamics. The analysis was conducted on six economically and ecologically important fish populations from cold temperate and sub‐arctic marine ecosystems. Our results underscore the importance of size for survival early in life. The comparative analysis suggests that size‐dependent mortality and density‐dependent growth frequently occur at a transition from pelagic to demersal habitats, which may be linked to competition for suitable habitat. The generality of this hypothesis warrants testing in future research.publishedVersio

Molecular Mechanics of the α-Actinin Rod Domain: Bending, Torsional, and Extensional Behavior

α-Actinin is an actin crosslinking molecule that can serve as a scaffold and maintain dynamic actin filament networks. As a crosslinker in the stressed cytoskeleton, α-actinin can retain conformation, function, and strength. α-Actinin has an actin binding domain and a calmodulin homology domain separated by a long rod domain. Using molecular dynamics and normal mode analysis, we suggest that the α-actinin rod domain has flexible terminal regions which can twist and extend under mechanical stress, yet has a highly rigid interior region stabilized by aromatic packing within each spectrin repeat, by electrostatic interactions between the spectrin repeats, and by strong salt bridges between its two anti-parallel monomers. By exploring the natural vibrations of the α-actinin rod domain and by conducting bending molecular dynamics simulations we also predict that bending of the rod domain is possible with minimal force. We introduce computational methods for analyzing the torsional strain of molecules using rotating constraints. Molecular dynamics extension of the α-actinin rod is also performed, demonstrating transduction of the unfolding forces across salt bridges to the associated monomer of the α-actinin rod domain

Ревматоидный артрит в реальной клинической практике. Результаты проекта «Компьютерные терминалы самооценки для пациентов с ревматическими заболеваниями» («ТЕРМИНАЛ-I»)

Objective: to describe the portrait of a patient with rheumatoid arthritis (RA) in real clinical practice, to assess disease activity from the point of view of a physician and a patient, functional status, quality of life (QOL), and the efficiency of the therapy performed.Patients and methods. The investigation enrolled 976 RA patients from a cohort of patients in the TERMINAL-I multicenter study, who, when visiting a rheumatologist, independently assessed the disease activity and QOL using a computer system (the «Computer Terminals of SelfAssessment for Patients with Rheumatic Diseases» project). The mean age of the patients was 52.30±13.3 years; women accounted for 85%; the median disease duration 8.0 [4.0; 14.0] years. Baseline clinical parameters and pharmacotherapy were evaluated for 6 months. The disease activity was determined by the DAS28 and RAPID-3 indices; functional status and quality of life were evaluated by the HAQ and the EQ-5D, respectively.Results. 83% of the RA patients were positive for rheumatoid factor and 60% were for anti-cyclic citrullinated peptide antibodies. There was a preponderance of patients with high (40.5%) and moderate (46.8%) RA activity; 6.9% were observed to have a low activity; 5.8% had clinical remission. The mean values of DAS28 and RAPID-3 were 4.7±1.3 and 13.7±3.6, respectively. Only 14.3% of patients had a good functional status that was comparable with the population-based control (HAQ≤0.5). The remaining patients were found to have a substantial decrease in joint functional parameters (median HAQ 1.88 [1.0; 2.5]) and EQ-5D QOL (0.60 [0.60; 0.74). Prosthetic joints were present in 7.4% of patients. At visit 1 to a rheumatologist, the therapy was changed in 15% of patients. During 6-month follow-up, conventional disease-modifying anti-rheumatic drugs were taken by almost all (91.2%) patients. Of them, 70.9% of the patients were treated with methotrexate (MTX): 77.0% received the latter at a dose of 15 mg/week and 23.0% had it at a dose of >15 mg (17.5 to 40 mg/week). Glucocorticoids could be stopped in 20.5% of the patients within six months. Tumor necrosis factor-α inhibitors and anti-B-cell therapy were used in 6.6 and 16.2% of patients, respectively. At 6-month follow-up (Visit 2), 54% of patients achieved a 20% clinical improvement in the ACR criteria. At the same time, the DAS28 scores decreased substantially from 4.5±1.2 to 3.8±1.1 (p = 0.0001). There was a minimal functional improvement in the HAQ index in 64% of patients and a better EQ-D QOL scores in 16%.Conclusion. The majority of RA patients who came to the rheumatologists showed high to moderate disease activity. This was due to long disease duration, inadequate MTX dose, and insufficient patient monitoring in real clinical practice. Introduction of a computer system for selfassessment of their health status by RA patients in an outpatient setting could improve the interaction of physicians, nurses, and patients, better monitor disease activity, and enhance therapeutic efficiency. Цель исследования – описание «портрета» пациента с ревматоидным артритом (РА) в реальной клинической практике, оценка активности заболевания с точки зрения врача и пациента, функционального состояния, качества жизни (КЖ) и эффективности проводимой терапии.Пациенты и методы. В исследование включено 976 пациентов с РА из когорты больных, входящих в многоцентровое исследование «ТЕРМИНАЛ-I», которые при обращении к ревматологу самостоятельно оценивали активность заболевания и КЖ с помощью компьютерной системы (проект «Компьютерные терминалы самооценки для пациентов с ревматическими заболеваниями»). Средний возраст пациентов составил 52,30±13,3 года, 85% – женщины, медиана длительности заболевания – 8,0 [4,0; 14,0] лет. Проводилась оценка базовых клинических параметров и фармакотерапии в течение 6 мес. Активность заболевания определялась по индексам DAS28 и RAPID-3, функциональный статус – по индексу HAQ, качество жизни – по EQ-5D.Результаты. 83% больных РА были позитивными по ревматоидному фактору и 60% – по антителам к циклическому цитруллинированному пептиду. Преобладали пациенты с высокой (40,5%) и умеренной (46,8%) активностью РА, у 6,9% отмечалась низкая активность, у 5,8% –клиническая ремиссия. Среднее значение индекса DAS28 составило 4,7±1,3, RAPID-3 – 13,7±3,6. Только 14,3% пациентов имели хорошее функциональное состояние, сравнимое с популяционным контролем (HAQ ≤0,5). У остальных больных отмечалось значительное снижение показателей функции суставов (медиана HAQ 1,88 [1,0; 2,5]) и КЖ по индексу EQ-5D (0,60 [0,60; 0,74]). Протезированные суставы имели 7,4% больных. При 1-м визите к ревматологу терапия была изменена у 15% пациентов. В течение 6 мес наблюдения практически все пациенты (91,2%) получали стандартные базисные противовоспалительные препараты. Из них 70,9% пациентов находились на терапии метотрексатом (МТ): 77,0% получали его в дозе 15 мг/нед и 23,0% – >15 мг (от 17,5 до 40 мг/нед). 20,5% пациентам в течение полугода удалось отменить глюкокортикоиды. Ингибиторы фактора некроза опухоли α использовали 6,6% больных, анти-В-клеточную терапию – 16,2%. После 6 мес наблюдения (2-й визит к врачу) 20% клиническое улучшение по критериям ACR достигнуто у 54% больных. При этом отмечалось значительное снижение индекса DAS28 (с 4,5±1,2 до 3,8±1,1 балла; p=0,0001). Минимальное функциональное улучшение по индексу HAQ зафиксировано у 64% пациентов, улучшение КЖ по EQ-5D – у 16%.Выводы. Высокая и умеренная активность заболевания, снижение показателей КЖ были характерны для большинства пациентов с РА, обратившихся к ревматологу. Это было связано с большой длительностью заболевания, неадекватной дозой МТ и недостаточным мониторингом пациентов в реальной клинической практике. Введение компьютерной системы самооценки состояния здоровья пациентов с РА на поликлиническом уровне позволило улучшить взаимодействие врачей, медицинских сестер и пациентов, более качественно контролировать активность заболевания и повысить эффективность терапии.

Продолжительность жизни больных метастатическим раком мочевого пузыря в Российской Федерации: результаты многоцентрового регистрового исследования URRU

Background. Data on the overall survival (OS) of patients with metastatic bladder cancer (BCa) is rarely published.The objective of the URRU register study is to assess OS and collect information on the administration of different treatments in patients with metastatic BCa in routine clinical practice in Russia.Materials and methods. Patients were retrospectively identified in 9 oncology centers in different regions of Russia and included in the study if they were diagnosed with metastatic BCa between January 2017 and January 2018. We collected anonymized data online, including demographic characteristics of patients, details of their therapy, and outcomes.Results. This study included 246 patients. Their mean age upon the diagnosis of metastatic BCa was 72 years with 60.6 % of patients over 70 years of age. The proportion of males was 74.8 %. The histological subtype of BCa (urothelial carcinoma, etc.) was identified in 70.3 % of cases. Ninety-two patients (37.4 %) received pharmacotherapy. The most common treatment option was chemotherapy (76 %); the most common drug combination was gemcitabine and cisplatin (41.3 %). Immunotherapy was used in 19.6 % of patients; 13.6 % of participants received more than two lines of therapy. Three-year OS rate was 10.6 %; median OS was 7 months (95 % confidence interval (CI) 5.4-8.6). Patients receiving systemic therapy demonstrated significantly longer survival than those receiving no therapy (21 months; 95 % CI 17.38-24.62 vs 3 months; 95 % CI 1.79-4.22; p <0.0001). Patients receiving immunotherapy had better survival than individuals receiving chemotherapy (median OS 34.5 months vs 18 months; p = 0.003).Conclusion. The survival rates in the URRU study were relatively low, which can be attributed to the fact that only one-third of patients received pharmacotherapy and very few patients received immunotherapy. Second and subsequent lines of therapy were rarely used in patients with progressive disease. The implementation of novel treatments, including immune checkpoint inhibitors, will increase the survival of BCa patients.Введение. Данные по общей выживаемости (ОВ) пациентов с метастатическим раком мочевого пузыря (РМП) публикуются редко.Цель регистрового исследования URRU - оценка ОВ и сбор сведений по применению разных вариантов терапии метастатического РМП в условиях реальной клинической практики в российской популяции пациентов.Материалы и методы. Пациентов ретроспективно идентифицировали в 9 онкологических центрах в разных регионах России и включали в исследование, если диагноз метастатического РМП был установлен в период с января 2017 г. по январь 2018 г. Анонимные сведения собирали онлайн, регистр охватывал демографические характеристики, а также данные по терапии и исходам.Результаты. В исследование для анализа были включены 246 больных. Средний возраст на момент постановки диагноза метастатического РМП составил 72 года, при этом 60,6 % пациентов были старше 70 лет. Мужчин было 74,8 %, гистологический подтип РМП (уротелиальный или др.) верифицирован в 70,3 % случаев. Лекарственную терапию проводили 92 (37,4 %) пациентам. Самым часто применявшимся вариантом лечения была химиотерапия (76 %), а наиболее часто назначаемой комбинацией - гемцитабин и цисплатин (41,3 %). Иммунотерапию проводили у 19,6 % пациентов. Более 2 линий терапии получили 13,6 % больных. Трехлетняя ОВ составила 10,6 %, медиана ОВ - 7 мес (95 % доверительный интервал (ДИ) 5,4-8,6). Медиана ОВ (21 мес; 95 % ДИ 17,38-24,62) у пациентов, получавших системную терапию, была значительно больше, чем у пациентов, у которых терапия не проводилась (3 мес; 95 % ДИ 1,79-4,22; p <0,0001). Пациенты, получавшие иммунотерапию, имели лучшие результаты по показателям выживаемости по сравнению с таковыми у больных, у которых проводилась химиотерапия (медиана 0В 34,5 мес против 18 мес; p = 0,003).Заключение. Показатели ОВ в исследовании URRU являются скромными, что можно объяснить назначением лекарственного лечения только трети пациентов, низкой частотой применения иммуноонкологических препаратов, редким назначением терапии во 2-й и последующих линиях при прогрессировании заболевания. Внедрение новейших вариантов лекарственного лечения, в том числе ингибиторов контрольных точек, будет способствовать увеличению продолжительности жизни больных

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Background: Activated phosphoinositide-3-kinase d syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain of-function (GOF) disease; and identify predictors of severity in APDS. Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients. (J Allergy Clin Immunol 2023;152:984-96.