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.

4-WEEK OPEN-LABEL CONTROLLED RANDOMIZED COMPARATIVE STUDY OF THE INJECTABLE AND TABLETTED FORMULATIONS OF METHOTREXATE IN RHEUMATOID ARTHRITIS

Objective: to estimate the advantages and disadvantages of using the injectable formulation of methotrexate (MT) (Methoject (MTJ)) in rheumatoid arthritis (RA) in clinical practice. Subjects and methods. A 24-week open-label controlled randomized comparative study evaluated the therapeutic and side effects of MTJ and methotrexate tablets in RA and clarified whether MTJ treatment might be continued if its tabletted formulation was discontinued because of adverse reactions. Results and discussion. MTJ was found to be more effective than the tabletted formulation of MT and as a whole; and following 3-month therapy, more patients receiving MTJ achieved an ACR20 response. The advantage of MTJ was also retained 6 months after therapy. Higher transaminase levels were noted in 2 patients, one in each group. Switching from MT to MTJ noticeably reduced the number of adverse reactions in the majority of patients from an additional group. Conclusion. As compared to MT, MTJ used in RA patients is more effective when given in an equivalent dose, exerts a therapeutic effect more rapidly, and induces adverse gastrointestinal reactions less frequently

POSSIBILITIES FOR PRESERVING THE RESULTS OF TREATMENT IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AFTER DOSE REDUCTION AND/OR DISCONTINUATION OF BIOLOGICAL AGENTS: A REMARCA STUDY

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

USE OF SUBCUTANEOUS METHOTREXATE FOR THE TREATMENT OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: THE REMARCA TRIAL

The early administration of methotrexate (MTX) and the use of its high (by the rheumatology practice standards) doses contribute to the enhanced efficiency of therapy and the reduced severity of rheumatoid arthritis (RA). One of the important merits of MTX in the treatment of RA is the possibility of adjusting its dose and choosing its (oral or subcutaneous) administration routes, which makes it possible to individualize treatment. Particular emphasis has been recently placed just on a subcutaneous MTX formulation that creates prerequisites for substantially improving the efficiency of RA therapy. The paper gives the data of the REMARCA (Russian investigation of methotrexate and biologicals for early active arthritis) trial assessing the results of RA treatment in the use of the subcutaneous MTX dosage form as a first-line drug and in the elaboration of management tactics for this disease.Subjects and methods. The investigation included 191 patients (34 men and 157 women) with active RA; of whom 51.8% had very early RA (< 6 months' disease duration). 115 patients with RA completed a 24-month follow-up period; and their data were analyzed in more detail.Results and discussion. The findings may substantiate treatment policy based on the prescription of subcutaneous MTX (without previously administering its oral formulation) in patients with early RA and high disease activity, starting the drug at 15 mg/week and rapidly escalating with the highest tolerable doses during 4-8 weeks, which allows remission (or low disease activity) in the majority of patients without using glucocorticoids and biological agents

Evaluation of rituximab therapy in real clinical practice (according to the OREL registry of patients with rheumatoid arthritis

Objective: to analyze therapy with rituximab (RTM) in real clinical practice according to the data available in OREL registry of patients with active rheumatoid arthritis (RA).Subjects and methods. The analysis included 349 patients. All the patients received RTM: 340 – the original drug (MabThera®) and 9 – the biosimilar Acellbia®. 263 patients (75.4%) received RTM in combination with disease-modifying anti-rheumatic drugs (DMARDs) and 86 (24.6%) – RTM as monotherapy.Results and discussion. Of the 349 patients included in the analysis, 272 (77.9%) patients received RTM as the first biologic agent (BA) (263 patients were treated with the original drug and 9 – with the biosimilar) and 77 (22.1%) patients had previously used the BA. The majority of patients (n=205 (58.7%)) received three or more; 109 (31.2%) patients – one, and 35 (10%) – two RTM courses of RTM therapy. RTM caused a significant reduction in disease activity just after the first therapy course and in the levels of acute-phase reactants (C-reactive protein (CRP) and ESR); after the fifth therapy course, median CRP concentration decreased by 1.4 times and amounted to 7 [1.2; 17.9] mg/l and that of ESR reduced by 1.8 times and was 10 [5; 20] mm/hr (p<0.05).Conclusion. The analysis of RTM therapy in RA patients in real clinical practice demonstrated that in most cases RTM was given as the first BA, in combination with DMARDs, the main agent of which was methotrexate. The use of RTM was accompanied by a significant reduction in disease activity and in the serum levels of acute-phase reactants and autoantibodies

THE FIRST RUSSIAN STRATEGIC STUDY OF PHARMACOTHERAPY FOR RHEUMATOID ARTHRITIS (REMARCA TRIAL): RESULTS OF 12-MONTH TREATMENT IN 130 PATIENTS

To introduce treat-to-target recommendations is an important task of modern rheumatology; however, there is still a diversity of serious problems relating to a scientific rationale and a clinical one for this strategy and to the possibilities of its implementation in real clinical practice, in the rheumatology service of the Russian Federation in particular, by taking into account the specific features of funding for high-tech medical care.Objective: to determine the efficiency and safety of combined therapy with subcutaneous methotrexate (MT) and biological agents (BA) when using the treat-to-target strategy in patients with active early and extended-stage rheumatoid arthritis (RA) who have risk factors for a poor prognosis.Subjects and methods.The results of the REMARCA (Russian InvEstigation of MethotrexAte and biologicals in eaRly aCtive inflammatory Arthritis) trial of 130 patients followed up for 12 months or more were given. There was a female preponderance; mean age 48.9±13.9 years, rheumatoid factor positivity (86.9%); anti-cyclic citrullinated peptide antibody positivity (89.2%). Seventy patients formed a subgroup of early RA (disease duration ≤6 months (mean 4.17±1.39 months)); 60 patients were a subgroup of advanced-stage RA (disease duration >6 months (mean 30.8±32.7 months)). In all the patients, therapy was initiated by using subcutaneous MT with its rapid dose escalation up to 20–30 mg/week and the achievement of the treatment goal (low disease activity or remission) was checked every 3 months and depending on the result a decision had been taken to add or not to add a biological agent (BA) (a tumor necrosis factor inhibitor or abatacept). If the former was insufficiently effective, it was substituted for a BA from another class.Results. Subcutaneous MT monotherapy provided remission or low disease activity in 49 (37.7%) patients; a BA was given to 81 (62.3%) patients. Following 6 and 12 months, low activity or remission according to SDAI was observed significantly more frequently in the patients who continued subcutaneous MT monotherapy than in those who received combined therapy with MT and BA. The similar results were obtained by using DAS28 and CDAI to assess a trend in disease activity. After 6- and 12-month follow-up, there was a significantly more marked decline of tender joint count, SDAI and CDAI in early RA than in advanced-stage RA; at 12 months, SDAI remission rate was 45.7% and 28.3%, respectively (p=0.047).Conclusion. The treat-to-target strategy should be used in real clinical practice and can yield spectacular results. Active therapy with subcutaneous MT with its rapid dose escalation to the maximally tolerable dose allows identification of a considerable group of patients (38%) with a good response to MT monotherap

THE FIRST RUSSIAN STRATEGIC STUDY OF PHARMACOTHERAPY FOR RHEUMATOID ARTHRITIS (REMARCA TRIAL): RESULTS OF 12-MONTH TREATMENT IN 130 PATIENTS

To introduce treat-to-target recommendations is an important task of modern rheumatology; however, there is still a diversity of serious problems relating to a scientific rationale and a clinical one for this strategy and to the possibilities of its implementation in real clinical practice, in the rheumatology service of the Russian Federation in particular, by taking into account the specific features of funding for high-tech medical care. Objective: to determine the efficiency and safety of combined therapy with subcutaneous methotrexate (MT) and biological agents (BA) when using the treat-to-target strategy in patients with active early and extended-stage rheumatoid arthritis (RA) who have risk factors for a poor prognosis. Subjects and methods. The results of the REMARCA (Russian InvEstigation of MethotrexAte and biologicals in eaRly aCtive inflammatory Arthritis) trial of 130 patients followed up for 12 months or more were given. There was a female preponderance; mean age 48.9±13.9 years, rheumatoid factor positivity (86.9%); anti-cyclic citrullinated peptide antibody positivity (89.2%). Seventy patients formed a subgroup of early RA (disease duration ≤6 months (mean 4.17±1.39 months)); 60 patients were a subgroup of advanced-stage RA (disease duration >6 months (mean 30.8±32.7 months)). In all the patients, therapy was initiated by using subcutaneous MT with its rapid dose escalation up to 20–30 mg/week and the achievement of the treatment goal (low disease activity or remission) was checked every 3 months and depending on the result a decision had been taken to add or not to add a biological agent (BA) (a tumor necrosis factor inhibitor or abatacept). If the former was insufficiently effective, it was substituted for a BA from another class. Results. Subcutaneous MT monotherapy provided remission or low disease activity in 49 (37.7%) patients; a BA was given to 81 (62.3%) patients. Following 6 and 12 months, low activity or remission according to SDAI was observed significantly more frequently in the patients who continued subcutaneous MT monotherapy than in those who received combined therapy with MT and BA. The similar results were obtained by using DAS28 and CDAI to assess a trend in disease activity. After 6and 12-month follow-up, there was a significantly more marked decline of tender joint count, SDAI and CDAI in early RA than in advanced-stage RA; at 12 months, SDAI remission rate was 45.7% and 28.3%, respectively (p=0.047). Conclusion. The treat-to-target strategy should be used in real clinical practice and can yield spectacular results. Active therapy with subcutaneous MT with its rapid dose escalation to the maximally tolerable dose allows identification of a considerable group of patients (38%) with a good response to MT monotherapy