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.

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

TIME COURSE OF CHANGES IN BLOOD LIPID PARAMETERS IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS DURING TREAT-TO-TARGET ANTIRHEUMATIC THERAPY: ACCORDING TO 18-MONTH FOLLOW-UP FINDINGS

The mechanisms for lowering a cardiovascular risk (CVR) in patients with early rheumatoid arthritis (RA) when implementing the treat-to-target strategy remain inadequately investigated.Objective: to estimate the time course of changes in blood lipid parameters in patients with early RA during Treat-totarget antirheumatic therapy at an 18-month follow-up.Subjects and methods. Seventy-four patients (73% women; median age, 56 years) with early RA meeting the respective 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria and moderate or high activity (median DAS28-ESR score of 5.4) were examined within the framework of the REMARCA trial. After 6-month treatment, RA activity significantly reduced (p < 0.05). At months 6 to 18, no significant change in RA activity was recorded. After 18 months, remission was observed in 31 (42%) patients: in 17 (55%) on methotrexate (MTX) monotherapy and in 14 (45%) on combined therapy with MTX and a biological agent. Blood lipid levels were determined at inclusion in the investigation, 6 and 18 months later. The values of lipid parameters were estimated in terms of the total CVR. 67.6% of the patients were classified as at very high CVR. At 18 months of treatment, 34 (46%) patients were treated with statins (median atorvastatin and rosuvastatin doses were 10 mg/day each).Results and discussion. Only 12% of the patients had optimal baseline values of just all lipid parameters. The concentration of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) correlated negatively with C-reactive protein (CRP) levels, DAS28-ESR, DAS28-CRP, and HAQ (p < 0.05). After 6-month treatment, there were increases in TC by 7%, LDL-C by 12.5%, and HDL-C by 19.7%, and a decrease in the atherogenic index by 16% (p < 0.05). ΔCRP negatively correlated with ΔTC, ΔLDL-C, and ΔHDL-C (r = -0.3; p < 0.05). A correlation of TC and LDL-C with inflammation markers broke off in the presence of lower RA activity; the investigators began recording a relationship of these lipid parameters to traditional CVR factors. Between 6th and 18th month of treatment, there was no significant change in lipid parameters. Statin therapy resulted in no considerable change in lipid concentrations.Conclusion. The level of lipids negatively correlates with disease activity in the patients with early RA. During antirheumatic treatment, the lipid concentrations are more elevated with a more intensive decrease in CRP levels. With lowered RA activity, the level of lipids correlates with traditional CVR factors more strongly than with inflammation markers

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

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 possibilitiesof 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 anti body 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 insufficientlyeffective, 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  ubcutaneous 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 was45.7% and 28.3%, respectively (p=0.047).Conclusion. The treat-to-target strategy should be used in real clinical practiceand 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

EFFECT OF «TREAT-TO-TARGET» ANTIRHEUMATIC THERAPY ON DIASTOLIC DYSFUNCTION OF THE LEFT AND RIGHT VENTRICLES IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS DURING 18 MONTHS OF OBSERVATION

Aim. To study the effect of «treat-to-target» antirheumatic therapy on diastolic dysfunction of the left (DDLV) and right (DDLV) ventricles in patients with early rheumatoid arthritis (RA) during 18 months of observation.Material and methods. The study included patients with early RA (n=66; 71% women; age - 56 [46; 61] years) with moderate/high activity (DAS28 5.3 [5.0; 6.2]), seropositive on rheumatoid factor (77%) and/or cyclic citrullinated peptide antibodies (100%), disease modifying anti-rheumatic drugs (DMARD) and glucocorticoids naive. Treatment with methotrexate (MTX) with the escalation of the dose up to 25-30 mg/week subcutaneously was initiated in all the patients. After 3 months in 47 (71%) patients biologics were added to MTX due to its inefficiency. In 18 months remission of RA was achieved in 44% of the patients. 51 (77%) patients had a cardioprotective therapy. The target blood pressure (BP) level was achieved in 38 (58%) patients. Evaluation of traditional cardiovascular risk factors, 24-hour BP monitoring and echocardiography were performed in all patients initially and in 18 months of MTX/MTX + biologics use.Results. After 18 months DDLV incidence decreased by 7% (from 49% to 42%; p&gt;0.05) and DDRV incidence decreased by 5% (from 24% to 17%; p&gt;0.05). A more significant decrease in DDLV incidence [from 23 (62%) to 18 (49%)] and of DDRV incidence (from 12 (32%) to 6 (16%)] (р=0.05), was found in MTX + biologics group than in MTX only group [DDLV incidence remained unchanged - 7 (28%), and DDRV incidence increased from 3(12%) to 4 (16%); p&gt;0.05]. The normalization of left ventricle (LV) diastolic function in early RA patients depended primarily on the efficacy of antihypertensive treatment, and of right ventricle (RV) diastolic function - on the achievement of target BP level and RA remission. Reduced erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) plasma levels were associated with the improved LV diastolic function [E/A LV and ΔESR (r=-0,3; p&lt;0,04), E/A LV and CRP (r=-0,2; p&lt;0.05), A LV and ESR (r=0.3; p&lt;0.01)] and improved RV diastolic function [ΔA RV and ΔCRP (r=0.4; p&lt;0.003), ΔE RV and ΔCRP (r=0.3; p&lt;0.01), E/A RV and DAS28 (r=-0.5; p&lt;0.001), E/A RV and CRP (r=-0,3; p&lt;0.05)] by the 18th month of the study.Conclusion. In early RA patients after 18 months the downward trend of DDLV incidence and a significant reduction of DDRV incidence were found, more expressed in patients treated with MTX + biologics. The achievement of RA remission and target BP level is a prerequisite for the normalization of LV and RV diastolic function and slowing the progression of heart failure.</p