Безопасность долгосрочного применения ритуксимаба у пациентов с ювенильным идиопатическим артритом: результаты когортного ретроспективного исследования

Abstract

Juvenile idiopathic arthritis (JIA) is the most frequent rheumatic disease of childhood. The goal of juvenile arthritis therapy is to achieve durable clinical and laboratory remission and a good quality of life. Various groups of drugs are used in the treatment of JIA, one of which is the anti-CD20 drug rituximab. Rituximab causes B-cell depletion, which may lead to decreased immunoglobulin levels, decreased antigen-presenting function of B-lymphocytes and impaired T-cell response. The main side effects of rituximab administration are infusion reactions, hypogammaglobulinaemia, neutropenia and infectious complications. Safety studies of rituximab use have been conducted mainly in adult patients with rheumatoid arthritis, in paediatric patients with oncological diseases and diffuse connective tissue diseases. There have been no long-term safety studies of rituximab in children with JIA. Objective. To evaluate the safety of long-term use of rituximab in patients with juvenile idiopathic arthritis. Patients and methods. A cohort retrospective study of patients with JIA aged from 2 to 17 years with evaluation of adverse events on the background of rituximab therapy was carried out; the maximum duration of follow-up was 165 months. Rituximab was administered by intravenous drip at a dose of 375 mg/m2 body surface area by 4 weekly injections (61% of all courses given) or 2 injections of 1000 mg 2 weeks apart (29%). 4% had 1 administration per course; 6% had 3 consecutive weekly administrations. The indication for repeat rituximab administration and the number of administrations were determined on an individual basis. Safety was assessed by registration of adverse events (AEs) according to medical records; AEs registered during the patient's hospitalisation and anamnestic data on AEs during the interhospital period were taken into account; infectious, infusion and other AEs were considered separately. Results. Rituximab demonstrated a sufficiently high safety profile: 88/102 (86%) patients did not report any serious AEs (grade ≥3); life-threatening AEs (grade 4-5) were reported in 7/102 (7%) patients, included 4 episodes of severe pneumonia, 3 episodes of sepsis; their incidence was 2.5 cases per 100 PY. The incidence of infectious AEs was 57.4/100 patient-years; 85% of them corresponded to mild severity; most often infectious AEs were registered in the first year of rituximab therapy; pneumonia (16/100 PY) and ENT infections (11.3/100 PY) prevailed in the structure. Infusion reactions developed with an incidence of 34.8/100 PY, most frequently registered at the first rituximab administration and manifested as influenza-like syndrome (18.4/100 PY) and rash (10.3/100 PY). The incidence of neutropenia was 17/100 PY, erythropenia 0.7/100 patient-years; decreased blood immunoglobulin levels (IgA – 5.3 episodes, IgM – 6.7, IgG – 3.4/100 patient-years), increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity – 3.9/100 PY, 1 episode of increased serum urea levels. Conclusion. The use of rituximab in patients with JIA may be accompanied by the development of AEs, which include infusion reactions, infectious complications, cytopenias, decreased level of immunoglobulins in blood, increased activity of ALT and AST. Implementation of the algorithm for the management of patients with JIA under rituximab treatment into clinical practice will allow to ensure monitoring of AEs, their detection at early stages, timely initiation of adequate therapy to prevent the development of severe complications. Key words: juvenile idiopathic arthritis, safety of therapy, rituximab, adverse events, infusion reactions, infectious complications