The effectiveness of rituximab in the treatment of systemic juvenile idiopathic arthritis
Authors:   National Medical Research Center of Children's Health, Moscow, Russian Federation, Kondrateva N.M. , Dvoryakovskaya T.M. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Association of Pediatric Rheumatologists, Moscow, Russian Federation, Kriulina T.Yu. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Isaeva K.B. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Chomakhidze A.M. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Lomakina O.L. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Chibisova K.V. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Kriulin I.A. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Krekhova E.A. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Tsulukiya I.T. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Botova M.S. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Shingarova M.Sh. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Kokina M.Yu. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Semikina E.L. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Akulova S.S. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Tepaev R.F. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Z.A.Bashlyaeva Children’s City Clinical Hospital, Moscow, Russian Federation, Alexeeva E.I. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Association of Pediatric Rheumatologists, Moscow, Russian Federation
Published: February 2024

Systemic juvenile idiopathic arthritis (syn.: juvenile arthritis with systemic onset; hereinafter referred to as sJIA) is one of the most severe variants of juvenile arthritis, in which at the beginning of the disease it is often not joint damage that comes to the fore, but systemic manifestations such as fever, rash, hepatosplenomegaly, lymphadenopathy and serositis. Tumor necrosis factor-α (TNF-α) inhibitors, successfully used in the therapy of JIA without systemic manifestations, are not effective in most patients with JIA. Thus, according to the BIKER registry (Germany), remission was registered in 36% of patients with sJIA treated with TNF-α inhibitors [1]. According to guidlines, biological therapy of the first line for sJIA are monoclonal antibodies to the interleukin-6 receptor (tocilizumab) or to interleukin-1β (kanakinumab) [2, 3]. The high effect of the use of tocilizumab and kanakinumab in children with sJIA has been proven in clinical studies and clinical practice, However, 15-30% of patients develop their primary or secondary inefficiency, which makes it relevant to consider another therapeutic option for this category of patients, which may be rituximab– a chimeric monoclonal antibody to CD20+ B lymphocytes. Objective. To evaluate the effectiveness of chimeric monoclonal antibody to CD20+ B lymphocytes (rituximab) in the treatment of systemic juvenile idiopathic arthritis. Patients and methods. A retrospective cohort study of the medical records of 69 patients with sJIA aged 2 to 17 years (8.4 (IQR 5.2–13.3) years) treated with rituximab (76 prescriptions) was conducted. The duration of the disease was 3.3 (IQR 1.74–7.25) years. All patients before the appointment of rituximab received glucocorticosteroids (GCS), disease-modifying antirheumatic drugs (BMPRP), 33/69 (48%) – GIBP with a different mechanism of action. Inefficiency of GCS, BMPRP and GIBP was registered in all patients. Rituximab was administered intravenously at a dose of 375 mg / m2 of body surface area by 4 weekly injections (in 62/76 (82%) cases) or 2 injections of 1000 mg with an interval of 2 weeks. (in 11/76 (14%) cases). In 1 case, rituximab was administered once at a dose of 375 mg/m2 due to the development of acute intestinal infection after 1 administration, a repeat course was carried out after 3 months; in 2 cases, rituximab was administered at a dose of 375 mg/m2 for 3 consecutive weeks due to the development of infectious complications (ARVI and pneumonia). The need for repeating the course and its volume were determined depending on the activity of the disease, the number of B lymphocytes, and the presence of infectious complications. The average number of courses per 1 patient was 3 (IQR 1-4). The effectiveness of rituximab was evaluated after 1, 3, 6, 12 months. from the first administration, then every 6 months until the drug is discontinued, switching to another biological therapy or the patient reaches the age of 18 years. After 1, 3, 6 months, the effectiveness was evaluated, respectively, in 67 patients (74 cases), 66 patients (73 cases), 63 patients (68 cases), after 12 months – in 53 patients (54 cases), after 24, 36 and 48 months – in 44/44, 31/31, 22/22 patients/cases, respectively. The maximum duration of follow-up was 165 months (13.75 years) since the first administration of rituximab. The effectiveness was evaluated according to the criteria of the American College of Rheumatology for Pediatric Patients (ACRpedi30/50/70/90). The criteria for achieving the stage of inactive disease were the value of the JADAS71 index <1 and the criteria for inactive disease/remission of C.Wallace. The target points are to achieve a 50% improvement according to the ACRpedi criteria after 3 months and the stage of inactive disease according to the C.Wallace criteria after 6 months. Results. A significant decrease in the activity of sJIA (the number of systemic manifestations, joints with active arthritis, the JADAS71 disease activity index, the number of leukocytes, blood platelets, serum concentration of C-reactive protein, erythrocyte sedimentation rate) was recorded as early as 1 month after the first administration of rituximab. After 3 months, improvement according to the criteria of ACRpedi30/50/70/90 It was registered in 84/73/48/29% of cases, after 6 and 12 months – in 78/70/49/32% and 80/69/54/32% of cases, after 24, 36 and 48 months – in 77/77/66/48%, 87/84/68/52% and 86/86/82/68% of cases, respectively.The stage of inactive disease according to C.Wallace criteria was registered in 43% after 6 months, in 39% after 12 months, in 59% after 24 months, in 52 and 77% of cases after 36 and 48 months, respectively. During the observation period (48 months) The stage of inactive disease / remission according to C.Wallace criteria was achieved in 41/69 patients (59%), remission in 36/69 (52%) (76 cases, 47%). The median duration of remission in these patients (n = 36) was 19.5 (IQR 7 – 26.5) [1.5–158] months. Within 48 months, oral GCS was canceled in 15/49 (45.6%) cases. For the rest of Нациоthe patients, the daily dose of oral corticosteroids was reduced to minimum values – from 0.39 mg/ kg/ day (IQR 0.26–0.79) to 0.09 mg/kg/day (IQR 0.07–0.14). Oral corticosteroids were prescribed de novo in 4 cases. During 12 months, pulse therapy with GCS, which was performed before the start of rituximab therapy, was discontinued in 26/29 (98%) cases. Conclusion. The use of rituximab in patients with SJIA who did not respond to previous therapy with other biologic medications showed quite high efficacy: improvement of joint status, relief of systemic manifestations, reduction of laboratory activity of the disease; it allowed to reduce the dose of GCS for oral administration, which reduces the likelihood of side effects. Currently, despite the presence of other GIBPS, rituximab is certainly a possible treatment option for systemic-onset juvenile arthritis resistant to other biological therapies. Key words: systemic juvenile idiopathic arthritis, rituximab, effectiveness of therapy