SAFETY OF USING METHOTREXATE SOLUTION FOR SUBCUTANEOUS INJECTIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Objective: to evaluate the safety of treatment with methotrexate (MT) solution for subcutaneous injections in patients with rheumatoid arthritis (RA).Subjects and methods. 237 RA patients enrolled in the study within the REMARCA protocol were given MT solution for subcutaneous injections (Metoject) to assess the standard parameters of therapy safety.Results. Overall, adverse events (AE) were noted in 49 (21%) patients. In 30 (30%) of them RA duration was less than 6 months (Group 1) and in 19 (14%) – more than 6 months (Group 2), in most cases average MT dose was 20.9±3.45 mg/week. Elevation of alanine aminotransferase and aspartate aminotransferase levels, nausea, postinjection reactions, alopecia, rash, infections, and leukopenia, were common (> 1%, but <10%); diarrhea, metallic taste in the mouth, soft tissue abscess/infiltration developing far from the injection site, were uncommon (the WHO term corresponding to 0.1–1%). AE required MT discontinuation in 4.2% of the patients.Conclusion. The results of the study allow discussing subcutaneous MT administration before treatment with biologicals, which makes it possible not only to reduce financial expenditures, but also to improve patient safet

THE RESULTS OF STUDYING OF THE MATERIAL FROM THE PATIENTS WITH SUSPECTED SEVERE ACUTE RESPIRATORY SYNDROME IN THE FAR EAST OF RUSSIA

During April-July, 2003 39 specimens of clinical material from six patients and three dead men with suspected «atypical pneumonia» who were detected on the territory of Khabarovsk, Primorski and Sakhalin regions were investigated. The inoculation of clinical material to cell culture Vero E6 did not show the cytopathogenic effect for coronavirus SARS. The amplificate with sought for molecular weight was obtained in RT-PCR assay with primers SAR1 and BNI in sputum and blood specimens of one of the patients, but it was not cDNA of coronavirus SARS. As a result of additional studies there were established the following diagnosis: HFRS, bronchopneumonia with Clebsiella etiology (postmortem) and leptospirosis (postmortem). The terminal diagnosis for the rest patients were: bronchopneumonia of inferior lobes (3), maxillary sinusitis, ARVI and toxocariasis

Application of Dot-Immunoassay for Detection of Plague Agent Antigens in the Field Samples

CFU/ml) and soluble antigens (FI) − ≥ 4.8 ng/ml and high specificity, confirmed by the absence of false-positive reactions with five heterologous microorganisms. The test-systems were used for Y. pestis antigen detection in field material from the territory of the Altai mountain natural plague focus by dot-immunoassay with comparison of the received results in passive hemagglutination reaction. Test-systems possessed a number of advantages as compared to routine serological reactions and could be applied with success by practical public health services both in stationary and field conditions

Results of Monitoring over and Biological Properties of <I>Vibrio cholerae</I> Isolated from Ambient Environment Objects in the Khabarovsk Territory

genotype and a unique MLVA profile. The results of the monitoring indicated that there were optimal for V. cholerae accumulation in surface water reservoirs conditions and it was necessary to enhance measures for cholera prophylaxis in the post-flood period

Основания для отмены базисных противовоспалительных препаратов , генно-инженерных биологических препарато в и тофацитиниба при ревматоидном артрите

Objective: to analyze the reasons for discontinuation of traditional disease-modifying antirheumatic drugs (tDMARDs), biologic agents (BAs), and tofacitinib (TOFA) in patients with rheumatoid arthritis (RA) in real clinical practice.Patients and methods. The authors carried out a retrospective analysis of the data of the patients treated with tDMARDs, BAs, and TOFA, who had been included by the physicians of the V.A. Nasonova Research Institute of Rheumatology (RIR) in the all-Russian register of patients with RA (Group 1) in January 1, 2016 to November 1, 2018, the data of a pharmacology history (information about inefficacy (IE) and adverse reactions (ARs) due to the use of tDMARDs and BAs) in RA patients admitted to the V.A. Nasonova RIR during 2011–2016 for high-tech medical care (Group 2).Results. The main reasons for discontinuation of tDMARDs, BAs, and TOFA were found to be their IE and ARs.Discussion. 20% of patients with early RA never achieve not only remission, but also minimal disease activity, despite the introduction of current guidelines for its treatment. It is believed that one of the potential causes of resistance to treatment in RA is the IE of traditionally used drugs, which is mediated by transporters (ABCB1 and ABCG2) that reduce their concentrations, causing outflow from the intracellular space. The great importance of these transporters in RA is that their substrates are widely used drugs, such as methotrexate, leflunomide, sulfasalazine, aminoquinoline drugs, and prednisolone. The function of ABCB1 and ABCG2 is shown to be increased in patients with active RA, i.e. the disease activity is closely related to this phenomenon.Conclusion. IE and ARs are the most common reasons for discontinuation of tDMARDs, BAs, and TOFA in patients with RA; further investigations are needed to clarify their possible mechanisms.Objective: to analyze the reasons for discontinuation of traditional disease-modifying antirheumatic drugs (tDMARDs), biologic agents (BAs), and tofacitinib (TOFA) in patients with rheumatoid arthritis (RA) in real clinical practice.Patients and methods. The authors carried out a retrospective analysis of the data of the patients treated with tDMARDs, BAs, and TOFA, who had been included by the physicians of the V.A. Nasonova Research Institute of Rheumatology (RIR) in the all-Russian register of patients with RA (Group 1) in January 1, 2016 to November 1, 2018, the data of a pharmacology history (information about inefficacy (IE) and adverse reactions (ARs) due to the use of tDMARDs and BAs) in RA patients admitted to the V.A. Nasonova RIR during 2011–2016 for high-tech medical care (Group 2).Results. The main reasons for discontinuation of tDMARDs, BAs, and TOFA were found to be their IE and ARs.Discussion. 20% of patients with early RA never achieve not only remission, but also minimal disease activity, despite the introduction of current guidelines for its treatment. It is believed that one of the potential causes of resistance to treatment in RA is the IE of traditionally used drugs, which is mediated by transporters (ABCB1 and ABCG2) that reduce their concentrations, causing outflow from the intracellular space. The great importance of these transporters in RA is that their substrates are widely used drugs, such as methotrexate, leflunomide, sulfasalazine, aminoquinoline drugs, and prednisolone. The function of ABCB1 and ABCG2 is shown to be increased in patients with active RA, i.e. the disease activity is closely related to this phenomenon.Conclusion. IE and ARs are the most common reasons for discontinuation of tDMARDs, BAs, and TOFA in patients with RA; further investigations are needed to clarify their possible mechanisms. Цель исследования – анализ причин отмены традиционных базисных противовоспалительных препаратов (тБПВП), генно-инженерных биологических препаратов (ГИБП) и тофацитиниба (ТОФА) у больных ревматоидным артритом (РА) в реальной клинической практике.Пациенты и методы. Проведен ретроспективный анализ данных о больных, получавших тБПВП, ГИБП и ТОФА, которые были внесены врачами НИИР им. В.А. Насоновой с 01.01 2016 г. по 01.11 2017 г. в общероссийский регистр больных РА (1-я группа); данных фармакологического анамнеза (информация о неэффективности – НЭ – и нежелательных реакциях – НР, – обусловленных применением тБПВП и ГИБП), у больных РА, госпитализированных в течение 2011–2016 гг. в НИИР им. В.А. Насоновой для получения высокотехнологичной медицинской помощи (2-я группа).Результаты. Установлено, что основными причинами отмены тБПВП, ГИБП и ТОФА являются НЭ и НР.Обсуждение. 20% больных ранним РА никогда не достигают не только ремиссии, но и минимальной активности болезни, несмотря на внедрение современных рекомендаций по лечению. Полагают, что одной из потенциальных причин резистентности РА к лечению является НЭ традиционно применяемых лекарственных препаратов, опосредуемая транспортерами (ABCB1 и ABCG2), которые снижают их концентрацию, вызывая отток из внутриклеточного пространства. Важное значение этих транспортеров при РА заключается в том, что субстратами для них являются такие широко используемые препараты, как метотрексат, лефлуномид, сульфасалазин, аминохинолиновые препараты, преднизолон. Показано, что у больных активным РА повышена функция ABCB1 и ABCG2, т. е. активность болезни тесно связана с этим феноменом.Выводы. Основными причинами отмены тБПВП, ГИБП и ТОФА у больных РА являются НЭ и НР, для уточнения их возможных механизмов необходимы дальнейшие исследования.Цель исследования – анализ причин отмены традиционных базисных противовоспалительных препаратов (тБПВП), генно-инженерных биологических препаратов (ГИБП) и тофацитиниба (ТОФА) у больных ревматоидным артритом (РА) в реальной клинической практике.Пациенты и методы. Проведен ретроспективный анализ данных о больных, получавших тБПВП, ГИБП и ТОФА, которые были внесены врачами НИИР им. В.А. Насоновой с 01.01 2016 г. по 01.11 2017 г. в общероссийский регистр больных РА (1-я группа); данных фармакологического анамнеза (информация о неэффективности – НЭ – и нежелательных реакциях – НР, – обусловленных применением тБПВП и ГИБП), у больных РА, госпитализированных в течение 2011–2016 гг. в НИИР им. В.А. Насоновой для получения высокотехнологичной медицинской помощи (2-я группа).Результаты. Установлено, что основными причинами отмены тБПВП, ГИБП и ТОФА являются НЭ и НР.Обсуждение. 20% больных ранним РА никогда не достигают не только ремиссии, но и минимальной активности болезни, несмотря на внедрение современных рекомендаций по лечению. Полагают, что одной из потенциальных причин резистентности РА к лечению является НЭ традиционно применяемых лекарственных препаратов, опосредуемая транспортерами (ABCB1 и ABCG2), которые снижают их концентрацию, вызывая отток из внутриклеточного пространства. Важное значение этих транспортеров при РА заключается в том, что субстратами для них являются такие широко используемые препараты, как метотрексат, лефлуномид, сульфасалазин, аминохинолиновые препараты, преднизолон. Показано, что у больных активным РА повышена функция ABCB1 и ABCG2, т. е. активность болезни тесно связана с этим феноменом.Выводы. Основными причинами отмены тБПВП, ГИБП и ТОФА у больных РА являются НЭ и НР, для уточнения их возможных механизмов необходимы дальнейшие исследования.

ВОЗМОЖНОСТИ СОХРАНЕНИЯ РЕЗУЛЬТАТОВ ЛЕЧЕНИЯ У БОЛЬНЫХ АКТИВНЫМ РЕВМАТОИДНЫМ АРТРИТОМ ПОСЛЕ СНИЖЕНИЯ ДОЗЫ И/ИЛИ ОТМЕНЫ ГЕННО-ИНЖЕНЕРНЫХ БИОЛОГИЧЕСКИХ ПРЕПАРАТОВ (ИССЛЕДОВАНИЕ РЕМАРКА)

Russian and international clinical recommendations postulate the possibility of withdrawal of biological agents in patients with rheumatoid arthritis (RA) after the achievement of clinical remission. But it is not clear what would be the results of implementation of these recommendations in clinical practice.Patients and methods. In REMARCA (Russian invEstigation of MethotrexAte and biologicals for eaRly aCtive Arthritis) trial 78 patients (66 females, 12 males, median age 53 years, duration of disease 7 months at inclusion), who were resistant to high doses of subcutaneous (SC) methotrexate (MTX), were treated by combination therapy with SC MT and biologics (adalimumab, certolizumab or abatacept). Patients were investigated every 3 months using DAS28-ESR, SDAI, CDAI indices as disease activity measures.Results. 30 (38.5%) patients (from 78) continued combination therapy. In 47 (60.3%) after achievement of remission or low disease activity (LDA) the therapy was modified to one of two options: 1) in 21 (26.9%) patients doses of biologics were tapered, in some cases to zero; 2) in 26 (33.3%) patients single-step discontinuation of biologics was performed. After 6 months among 47 patients with modification of therapy 27 (57.4%) maintained remission or LDA, in 20 (42.6%) deterioration observed, including 6 (12.8%) patients who lost remission but remained in LDA, and 14 (29.8%) flared (activity increased to moderate or high levels). First modification option was significantly superior to second option regarding the maintaining remission or LDA.Conclusion. In terms of maximum preservation of the results, optimal modification of treatment strategy is the tapering of the dose by the gradual increase in the period between injections of biologics, at least 12 months after reaching the state LDA or clinical remission. Российские и международные клинические рекомендации постулируют возможность отмены генно-инженерных биологических препаратов (ГИБП) у больных ревматоидным артритом (РА) после достижения клинической ремиссии. Но остается неясным, каковы будут результаты применения этих рекомендаций в реальной практике. Пациенты и методы. В рамках исследования РЕМАРКА (Российское исслЕдование МетотрексАта и генно-инженерных биологических препаратов при Раннем аКтивном Артрите) 78 пациентам с РА (66 женщин, 12 мужчин, на момент включения медиана возраста – 53 года, длительность болезни – 7 мес), резистентным к высоким дозам подкожного метотрексата (ПК МТ), была назначена комбинированная терапия ПК МТ и ГИБП (адалимумаб, цертолизумаб или абатацепт). Больных обследовали каждые 3 мес., активность оценивалась с помощью индексов активности DAS28-СОЭ, SDAI и CDAI. Период наблюдения составил не менее 24 мес. Результаты. Из 78 пациентов у 30 (38,5%) терапия комбинацией ГИБП + с-БПВП была продолжена. У 47 (60,3%) на фоне достижения ремиссии или стойкой низкой активности заболевания (НАЗ) проведена модификация лечения по одному из двух вариантов: 1) у 21 (26,9%) пациента – снижение дозы ГИБП, в том числе вплоть до полной отмены препарата; 2) у 26 (33,3%) пациентов – одномоментная отмена ГИБП. В течение последующих 6 мес из 47 больных с модификацией терапии у 27 (57,4%) сохранилось достигнутое состояние низкой активности заболевания (НАЗ) или ремиссии, у 20 (42,6%) состояние ухудшилось, в том числе 6 (12,8%) больных вышли из ремиссии, но остались в состоянии НАЗ, а у 14 (29,8%) наступило обострение (повышение активности РА до уровня умеренной или высокой). Первый вариант модификации достоверно превышал второй в отношении сохранения НАЗ или ремиссии. Выводы. С точки зрения максимального сохранения достигнутых результатов лечения оптимальная тактика модификации терапии состоит в снижении дозы путем постепенного увеличения периода между введениями ГИБП, вплоть до отмены, не менее чем через 12 мес после достижения состояния НАЗ или клинической ремиссии.

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The use of subcutaneous methotrexate from various manufacturers in real clinical practice: a comparative study

Background: Methotrexate is the main synthetic disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and other immunoinflammatory conditions. In the recent years, the subcutaneous form of methotrexate (SC MTX), particularly as ready-to-use syringes, has been increasingly used worldwide. Currently, several generics of SC MTX from different manufacturers are available. In literature we could not find any publications on the comparison of SC MTX generics.Aim: To evaluate the possibility to effectively use various SC MTXs for the treatment of RA and PsA in real clinical practice. Materials and methods: Patients older than 18 years old with a diagnosis of RA by ACR 1987 or ACR / EULAR 2010 criteria or diagnosis of PsA by CASPAR criteria with indications for SC MTX were included in this open-label 6-month observational study “Therapy of Rheumatoid Arthritis with Methotrexate in the Subcutaneous Form in Clinical Practice (TRAMPLIN)”. TRAMPLIN included two study periods: 1) a retrospective study of the safety of SC MTX from various manufacturers in clinical practice, according to patients' medical records; 632 patients (67.2% female, 32.8% male) on SC MTX were identified, and the number of adverse reactions recorded in the documentation (spontaneous reports) was determined; 2) a prospective study of the treatment duration and the reasons for the withdrawal of SC MTX from different manufacturers, which included 69 patients with RA and PsA. SC MTXs from three manufacturers were used in this study, namely Metoject (Medac GmbH, Germany); Métortrites (S.C. Rompharm Company S.R.L., Romania); Methotrexat Ebewe (Sandoz Pharmaceuticals D.D., Slovenia).Results: In the retrospective part of the study very few adverse events (AEs) were registered, which were related to SC MTX in the physician's opinion (41 patients, or 6.5%). Their incidence was higher in methotrexate-naïve patients. In the prospective part of the study at 3 months after the start of SC MTX therapy, 25 patients (36.2%) changed the treatment regimen (switched between the study drugs or to oral methotrexate). The main reasons for switching (20.3%) were “non-medical” events in the outpatients. AEs ranked second as a reason for the drug withdrawal (14.5%), irrespective of the manufacturer. At 6 month of the study, 38% patients were treated with Metoject, 30% with Methotrexat Ebewe, 28% with Métortrites, and 4% of patients  switched to oral methotrexate.Conclusion: This first Russian study of SC MTX generics from three different manufacturers confirmed a good SC MTX safety profile in a large clinical sample and showed good retention rates for therapy: by the end of the observation, 96% of the patients with available follow-up data remained on SC MTX. All three SC MTXs from different manufacturers were compatible in terms of safety, tolerability, and drug survival

COMPARATIVE EFFECTIVENESS OF THE COMBINATIONS OF DIURETICS AND DIHYDROPYRIDINE AND NONDIHYDROPYRIDINE CALCIUM ANTAGONISTS IN PATIENTS WITH ARTERIAL HYPERTENSION

In total, 54 patients, aged 42-65 years, with Stage II arterial hypertension (AH) were examined. At baseline and 16 weeks after the treatment phase, 24-hour blood pressure monitoring (BPM) and Doppler echocardiography were performed. The patients were randomised into 2 groups: Group 1 received combined therapy with indapamide and verapamil retard, while Group 2 was administered indapamide and amlodipine. Circadian BP rhythm was normalised in 82,8% and 76,0% of the patients from Groups 1 and 2, respectively. In Group 1, combined therapy was more effective among patients with Type I left ventricular diastolic dysfunction (LVDD), non-dipper circadian BP profile, and hyperkinetic circulation type. In Group 2, the therapy was more effective among participants with Type II-III LVDD and hypokinetic circulation type