rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.47360/1995-4484-2021-208-214rsp-3024Research ArticleПЕДИАТРИЧЕСКАЯ РЕВМАТОЛОГИЯPEDIATRIC RHEUMATOLOGYРитуксимаб при ревматических заболеваниях у детей: результаты ретроспективного исследования безопасности терапииRituximab for rheumatic diseases in children: Results of a retrospective study of the safety of therapyhttps://orcid.org/0000-0002-0513-6826КаледаМ. И.KaledaM. I.

Каледа Мария Игоревна

115522, Москва, Каширское шоссе, 34а

Maria I. Kaleda

115522, Moscow, Kashirskoye Highway, 34A

kaleda-mi@yandex.ruhttps://orcid.org/0000-0003-1842-0348НикишинаИ. П.NikishinaI. P.

115522, Москва, Каширское шоссе, 34а

Irina P. Nikishina

115522, Moscow, Kashirskoye Highway, 34A

https://orcid.org/0000-0002-6906-0621НиколаеваЕ. В.NikolaevaE. V.

115522, Москва, Каширское шоссе, 34а

Ekaterina V. Nikolaeva

115522, Moscow, Kashirskoye Highway, 34A

https://orcid.org/0000-0003-1648-7848ШаповаленкоА. Н.ShapovalenkoA. N.

115522, Москва, Каширское шоссе, 34а

Anna N. Shapovalenko

115522, Moscow, Kashirskoye Highway, 34A

https://orcid.org/0000-0002-2282-1745ФедоровЕ. С.FedorovE. S.

115522, Москва, Каширское шоссе, 34а

Evgeny S. Fedorov

115522, Moscow, Kashirskoye Highway, 34A

https://orcid.org/0000-0001-6183-8630ПачкорияТ. Н.PachkoriaT. N.

115522, Москва, Каширское шоссе, 34а

Tamari N. Pachkoria

115522, Moscow, Kashirskoye Highway, 34A

ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой»РоссияV.A. Nasonova Research Institute of RheumatologyRussian Federation202112052021592208214Copyright © Каледа М.И., Никишина И.П., Николаева Е.В., Шаповаленко А.Н., Федоров Е.С., Пачкория Т.Н., 20212021Каледа М.И., Никишина И.П., Николаева Е.В., Шаповаленко А.Н., Федоров Е.С., Пачкория Т.Н.Kaleda M.I., Nikishina I.P., Nikolaeva E.V., Shapovalenko A.N., Fedorov E.S., Pachkoria T.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/3024

Цель исследования: проанализировать безопасность ритуксимаба (РТМ) у детей с ревматическими заболеваниями.Материалы и методы. В ретроспективное исследование включен 81 пациент детского возраста с подтвержденным диагнозом иммуновоспалительного ревматического заболевания. Проанализированы данные по безопасности применения РТМ для всех пациентов, получивших по крайней мере одну инфузию препарата. Всем пациентам проводилось стандартное обследование в соответствии с диагнозом до назначения терапии РТМ. Доза РТМ на введение определялась из расчета 375 мг/м2 площади поверхности тела; препарат вводился один раз в неделю в течение от 1 до 4 последовательных недель в зависимости от количества лимфоцитов CD19, определяемого после инфузии, и переносимости терапии.Результаты. Среди пациентов, включенных в исследование, 38 (46,9%) имели системную красную волчанку (СКВ), 16 (19,75%) – ювенильный идиопатический артрит, полиартикулярный вариант (из них 14 (87,5%) имели РФ-позитивный вариант ЮИА), 9 (11,1%) – ЮИА с системным началом (сЮИА), 6 (7,4%) – системную склеродермию (ССД), 5 (6,2%) – первичный синдром Шегрена (СШ), 2 (2,5%) – ювенильный дерматомиозит (ЮДМ), 4 (4,9%) – смешанное заболевание соединительной ткани (СЗСТ), 1 (1,25%) – ливедоидную васкулопатию. 53 (65,4%) пациентам было проведено более одного курса терапии РТМ, максимальное количество курсов – 10. Нежелательные реакции (НР) легкой и средней степени тяжести были зарегистрированы у 23 (28,4%) пациентов, включая инфекции верхних дыхательных путей – у 7 (8,6%), инфекции мочевыводящих путей – у 2 (2,5%), легкие инфузионные реакции, которые не требовали прекращения терапии, – у 2 (2,5%), клинически незначимые нейтропении (I–II степени) – у 4 (4,9%), снижение уровня IgG – у 14 (17,5%) пациентов (медиана – 5,5 [4,0; 6,9] г/л). У 2 пациенток с сЮИА была зафиксирована стойкая гипогаммаглобулинемия на протяжении 3 и 5 лет соответственно после последней инфузии РТМ. Частота развития инфекций у пациентов с низким уровнем IgG составила 35,7%, у пациентов с нейтропенией инфекционных осложнений не зарегистрировано. Серьезные НР имели место у 16 (19,7%) пациентов: сепсис – у 4 (4,9%), пневмония – у 3 (3,7%), herpes zoster – у 1 (1,2%), серьезные инфузионные реакции – у 2 (2,5%), серьезные постинфузионные реакции в течение 3–10 дней – у 4 (4,9%) (у 3 (3,7%) пациентов – синдром активации макрофагов (САМ), у 1 (1,2%) – геморрагический васкулит). Летальный исход зафиксирован у 2 пациенток с СКВ, течение которой осложнилось САМ до начала терапии ритуксимабом, в связи с неэффективностью терапии. В целом различные НР были зарегистрированы у 55,6% пациентов с сЮИА, у 52,6% пациентов с СКВ, у 50% пациентов с ССД и ЮДМ и у 80% пациентов с первичным СШ. Прекращение терапии из-за серьезных НР наблюдалось у 15 (18,5%) пациентов.Заключение. Полученные данные свидетельствуют о высокой эффективности терапии РТМ при приемлемом профиле безопасности у детей с ревматическими заболеваниями. Применение РТМ требует тщательного мониторинга терапии, прежде всего с учетом риска инфекций, несмотря на то, что в данном исследовании частота инфекционных осложнений была низкой. Снижение уровня IgG наблюдалось у небольшой части пациентов и не коррелировало с частотой инфекций.

Objective: to analyze the safety of rituximab (RTM) in children with various rheumatic diseases.Materials and methods. The retrospective study included 81 pediatric patients with a confirmed diagnosis of rheumatic disease. Data on the safety of RTM were analyzed for all patients who received at least one infusion of the drug. All patients underwent a standard clinical, laboratory and instrumental examination in accordance with the verified diagnosis before the appointment of RTM therapy. The dose of RTM for administration was calculated based on 375 mg/m 2 of body surface area, the drug was administered once a week for 1 to 4 consecutive weeks, depending on the number of CD19 lymphocytes determined after the infusion, and the tolerability of therapy.Results. Among the patients included in the study, 38 (46.9%) were with systemic lupus erythematosus (SLE), 16 (19.75%) – with juvenile idiopathic arthritis (JIA), polyarticular variant (14 (87,5%) of them – RF-positive), 9 (11,1%) – with juvenile idiopathic arthritis with systemic onset (sJIA), 6 (7.4%) – with systemic sclerosus (SSc), 5 (6.2%) – with primary Sjogren’s syndrome, 2 (2.5%) – with juvenile dermatomyositis, 4 (4.9%) – with mixed connective tissue disease, and 1 – with livedoid vasculopathy. 53 (65.4%) patients underwent more than one course of RTM therapy, with a maximum of 10 courses. The total number of infusions was 198. The median time between each course was 182 [156–315] days. RTM was effective in 67 (95%) patients, ineffective in 2 (2.5%) patients with sJIA, 2 (2.5%) patients with SLE and macrophage activation syndrome (MAS).Adverse reactions (AE) of mild to moderate severity were reported in 23 (28.4%) patients, including upper respiratory tract infections – in 7 (8.6%), urinary tract infections – in 2 (2.5%), mild infusion reactions that did not require discontinuation of therapy – in 2 (2.5%), clinically insignificant neutropenia (I–II degree) – in 4 (4.9%), a decrease in IgG levels – in 14 (17.5%) patients (median – 5.5 [4.0; 6.9] g/l). Two patients with sJIA had persistent hypogammaglobulinemia for 3 and 5 years after the last RTM infusion, respectively. The incidence of infections in patients with low IgG levels was 35.7%, and no cases were registered in patients with neutropenia. Serious AE was reported in 16 (19.7%) patients: sepsis – in 4 (4.9%), pneumonia – in 3 (3.7%), herpes zoster – in 1 (1.2%), serious infusion reactions – in 2 (2.5%), serious postinfusion reactions within 3–10 days – in 4 (4.9%) (in 3 patients (3.7%) – MAS, in 1 (1.2%) – hemorrhagic vasculitis); death was registered in 2 cases of SLE and MAS (therapy of RTM was inefficient). In general, various AE were reported in 55.6% of patients with sJIA, 52.6% of patients with SLE, 50% of patients with SSc and juvenile dermatomyositis, and 80% of patients with primary Sjogren’s syndrome. Discontinuation of therapy due to serious AE was observed in 15 (18.5%) patients.Conclusion. Our study demonstrated that RTM therapy is highly effective with an acceptable safety profile in children with rheumatic diseases. The safety data obtained indicate the need for careful monitoring of therapy, primarily taking into account the risk of infection, despite the fact that in this study the frequency of infectious complications was not high. A decrease in IgG level was observed in a small proportion of patients and did not correlate with the incidence of infections.

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The authors declare that there are no conflicts of interest present.