Relationship of the clinical efficiency of tocilizumab therapy to the serum level of matrix metalloproteinase-3 in patients with rheumatoid arthritis


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AIM: To evaluate the impact of tocilizumab (TCZ) therapy on the level of matrix metalloproteinase-3 (MMP-3) 4, 24, and 48 weeks after treatment initiation in relation to the clinical efficiency of TCZ therapy by the Disease Activity Score (DAS28), the Clinical Disease Activity Index (CDAI), and the Simplified Disease Activity Index (SDAI)/MATERIAL AND METHODS: Forty-two rheumatoid arthritis (RA) patients who had received 6 intravenous infusions of TCZ 8 mg/kg at a 4-week interval during permanent therapy with disease-modifying anti-rheumatic drugs (DMARD) and glucocorticosteroids (GCS) were examined. Then TCZ was discontinued and the patients continued to receive the previous therapy with DMARD and GCS. The European League Against Rheumatism (EULAR) classification criteria, as well as SDAI and CDAI were used to evaluate the efficiency of TCZ therapy. The serum concentration of MMP-3 was measured by enzyme immunoassay using the test systems (Invitrogen, USA)/RESULTS: After 24 weeks of TCZ therapy (at 48 weeks following trial initiation), DAS28 was 4.69 (3.86; 5.44); the SDAI of 17.8 (10.7; 29.5) and the CDAI of 17.1 (7.2; 26.2) corresponded to moderate disease activity. At 48 weeks, DAS28 remission (<2.6 scores) remained in 5 (11.9%) patients; SDAI (≤3.3 scores) and CDAI (≤2.8 scores) remissions did in 3 (7.1%) and 4 (9.5%) patients, respectively. There was a significant reduction in MMP-3 concentrations at 4, 24, and 48 weeks of the therapy, which was 61, 73, and 49.4% of the baseline level. ROC analysis indicated that the normalization of MMP-3 levels in RA patients at 24 weeks of TCZ therapy (a cut-off ≤16.5 ng/ml) was associated with the maintenance of remission/low disease activity from SDAI and CDAI 24 weeks after the drug use (the area under the receiver operating curve was 0.762; 95% confidence interval: 0.548-0.976)/CONCLUSION: Analysis of the results of 48-week TCZ therapy suggests its ability to reduce the levels of markers of bone and cartilage destruction in patients with RA. Serum MMP-3 determination at 24 weeks of therapy may be useful in predicting the maintenance of remission/low activity from SDAI and CDAI after discontinuation of the drug.

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Взаимосвязь клинической эффективности терапии тоцилизумабом с уровнем матриксной металлопротеиназы-3 в сыворотке крови у больных ревматоидным артритом. - Резюме. Цель исследования. Оценить влияние терапии тоцилизумабом (ТЦЗ) на уровень ММП-3 через 4, 24 и 48 нед от начала лечения в сопоставлении с клинической эффективностью терапии ТЦЗ по индексам DAS28, CDAI и SDAI. Материалы и методы. Обследовали 42 больных РА, получивших по 6 инфузий ТЦЗ в дозе 8 мг/кг внутривенно с интервалом 4 нед на фоне стабильной терапии базисными противовоспалительными препаратами (БПВП) и глюкокортикостероидами (ГКС). Затем ТЦЗ был отменен, и пациенты продолжали получать прежнюю терапию БПВП и ГКС. Для оценки эффективности терапии ТЦЗ использовали критерии EULAR, а также индексы активности SDAI и CDAI. Концентрацию ММП-3 в сыворотке крови определяли методом иммуноферментного анализа с помощью тест-систем фирмы "Invitrogen" (США). Результаты. Через 24 нед после окончания терапии ТЦЗ (48-я неделя от начала исследования) индекс DAS28 составил 4,69 (3,86; 5,44) балла, SDAI - 17,8 (10,7; 29,5) балла, CDAI - 17,1 (7,2; 26,2) балла, что соответствовало умеренной активности заболевания. К 48-й неделе ремиссия по DAS28 (<2,6 балла) сохранялась у 5 (11,9%) пациентов, по SDAI (≤3,3 балла) - у 3 (7,1%), по CDAI (≤2,8 балла) - у 4 (9,5%). Достоверное уменьшение концентрации MMП-3 наблюдалось на 4, 24 и 48-й неделях терапии и составило 61, 73 и 49,4% от исходного уровня. По данным ROC-анализа, нормализация уровня ММП-3 у больных РА к 24-й неделе терапии ТЦЗ (точка разделения ≤16,5 нг/мл) ассоциировалась с сохранением ремиссии/низкой активности заболевания по индексам SDAI и CDAI через 24 нед после прекращения применения препарата (площадь по характеристической кривой 0,762 при 95% доверительном интервале от 0,548 до 0,976). Заключение. Анализ результатов терапии ТЦЗ через 48 нед свидетельствует о его способности снижать уровень маркеров костной и хрящевой деструкции у больных РА. Определение ММП-3 в сыворотке крови через 24 нед лечения может быть полезным для прогнозирования сохранения ремиссии/низкой активности по SDAI и CDAI после прекращения применения препарата.
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