Comparative evaluation of the efficacy of rituximab therapy in “biologically naïve” and “biologically non-naïve” patients with systemic juvenile idiopathic arthritis
Authors: Kondrateva N.M. ,   National Medical Research Center of Children's Health, Moscow, Russian Federation, Dvoryakovskaya T.M. , Kriulina T.Yu. , Isaeva K.B. , Chomakhidze A.M. , Lomakina O.L. , Chibisova K.V. , Kriulin I.A. , Krekhova E.A. , Fetisova A.N. , Tsulukiya I.T. , Botova M.S. , Shingarova M.Sh. , Kokina M.Yu. , Semikina E.L. , Akulova S.S. , Tepaev R.F. , 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,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   National Medical Research Center of Children's Health, Moscow, Russian Federation,   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,   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: July 2024

Systemic juvenile idiopathic arthritis (sJIA) is arthritis of one or more joints accompanied or preceded by confirmed intermittent fever of at least 3 days duration for at least 2 weeks in combination with one or more of the following features: transient (volatile) erythematous rash, generalized lymphadenopathy, hepatomegaly and/or splenomegaly, serositis. Prior to the invention of genetically engineered biological drugs (GEBDs), therapeutic options for patients with JIA were limited to the use of nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticosteroids (GCS), long-term and high-dose disease-modifying anti-rheumatic drugs (DMARDs). The first GIBPs (tumor necrosis factor-α (TNF-α) inhibitors) showed higher efficacy than standard DMARDs, but many patients experienced exacerbation of the disease. Since 2005, rituximab, a drug directed against the CD20 protein on the surface of B-lymphocytes, widely used in oncology for the treatment of lymphoma, has been used in patients with sJIA and has shown efficacy in refractory sJIA. With further advances in the pharmacological industry, more effective drugs for the treatment of SJIA, taking into account the main pathogenetic mechanisms of the disease development – interleukin-6 (IL-6) inhibitor tocilizumab and IL-1β inhibitor canakinumab – appeared. Currently, an approach to the therapy of juvenile idiopathic arthritis has been formulated, which is called "treat-to-target": achieving 50% improvement according to the pediatric criteria of the American College of Rheumatology (ACRpedi) by 3 months of therapy, the stage of inactive disease according to the criteria of C. Wallace – by 6 months and fever control after 1 week (for sUIA). Despite the introduction of IL-6 and IL-1 inhibitors into clinical practice, the effect is not achieved in all patients, which is the reason to search for other therapeutic approaches. Objective. To comparatively evaluate the efficacy of rituximab therapy in "biologically naive" (previously untreated with GEBDs) and "biologically non-naive" (previously treated with GEBDs) patients with sJIA resistant to therapy with GCS, DMARDs and GEBDs with other mechanisms of action. Patients and Methods. A retrospective cohort study of the medical records of 69 patients with sJIA aged 2 to17 years (Me 8.4 (IQR 5.2–13.3) years) with ineffective GCS, DMARDs, and GEBDs treated with rituximab was performed, of whom 36/69 (52%) were "biologically naive" and 33/69 (48%) were "biologically not naive." Mean ages of sJIA debut were 3 (2.19–7.39) and 3.39 (2.07–5.04) years, disease duration before rituximab prescription was 2 (0.9–4.83) and 5.6 (2.3–9.6) years; mean number of systemic manifestations per patient was 2.39 ± 0.16 and 2.08 ± 0.16; Me numbers of joints with active arthritis were 6 (4; 15) [0; 38] and 8 (4; 17) [0; 40]; JADAS71 index was 19.5 (14.9; 30.6) [9; 47] and 19.6 (14.2; 30.9) [5; 58.4] in "biologically naive" and "biologically non-naive" cases, respectively. Rituximab was administered by intravenous drip at a dose of 375 mg/m2 body surface area by 4 weekly infusions (in 62/76 (82%) of cases) or 2 infusions of 1000 mg 2 weeks apart (in 11/76 (14%) of cases). Me of courses per 1 patient was 3 (IQR 1–4). Efficacy was evaluated in 76 cases of rituximab administration (36/76 – biologically naive and 40/76 – "biologically non-naive") in 69 patients according to ACRpedi 30/50/70/90 criteria, JADAS71 index, and C.Wallace inactive disease/remission criteria. Target points – achievement of 50% improvement according to ACRpedi criteria in 3 months and inactive disease stage according to C.Wallace criteria in 6 months. After 1 month, efficacy was assessed in 74/76 (97%) cases (35/36 (97%) and 39/40 (98%) biologically naive and biologically non-naive respectively), after 3 months – in 73/76 (96%), (35/36 (97%) and 38/40 (95%)), after 6 months- in 68/76 (89%), (33/36 (92%) and 35/40 (88%)), after 12 months – in 54/76 (71%), (28/36 (78%) and 26/40 (65%)), after 24 months – in 44/76 (58%), (24/36 (67%) and 20/40 (50%)), after 36 months – 31/76 (41%), (19/36 (53%) and 12/40 (30%)), after 48 months – 22/76 (29%) cases (13/36 (36%) and 9/40 (23%) biologically naive and biologically non-naive cases, respectively). The maximum duration of follow-up was 165 months (13.75 years) from the first administration of rituximab. Results. ACRpedi 30/50/70/90 criteria were achieved in 89/77/51/34% of biologically naive and 79/68/45/24% of biologically not naive cases after 3 months; after 6 months – in 88/73/55/42% and 71/68/44/24% (p > 0.05); after 12 months, ACRpedi30/50/70 criteria were achieved in 82/71/64% and 77/65/42% of cases, respectively; ACRpedi 90 was significantly more frequently recorded in biologically naive than in biologically non-naive cases (46% vs. 15%, p = 0.03). After 24 months, ACRpedi 30/50/70/90 criteria were achieved in 79/79/67/50% and 75/75/65/45%; after 36 months – in 89/84/63/53% and 83/83/75/50%, after 48 months – in 92/92/85/77% and 78/78/78/56% of biologically naive and biologically non-naive cases, respectively (p > 0.05). Inactive disease stage according to C.Wallace criteria / JADAS71 index after 6 months was registered in 45/41% and 45/41% of biologically naive and biologically non-naive cases, respectively; after 12 months – in 43/46% and 35/31% (p > 0.05); after 24 months- in 63/67% and 45/50% (p = 0.39); after 36 months – in 47/47% and 58/58% (p = 0.82); after 48 months – in 85/85% and 67/56% (p = 0.63) of biologically naive and biologically non-naive cases of rituximab use, respectively. Conclusion. Monoclonal antibody to CD20+ B-lymphocytes – rituximab is a therapeutic option in biologically naive and biologically non-naive patients with sJIA, resistant to GCS, DMARDs, their combination with GEBDs, including the most advanced monoclonal antibodies to IL-6 receptor (tocilizumab) and monoclonal antibodies to IL-1β (canakinumab), which are included in the clinical guidelines as the first choice biological agents in patients with sJIA. Key words: rituximab, systemic juvenile idiopathic arthritis, comparative effectiveness