We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis (pJIA) with polyarticular or oligoarticular onset. Patients received 8 mg/kg tocilizumab every 4 weeks in the open-label studies: initial study (to week 12) and then an extension study (at least 48 weeks). Nineteen patients intractable to conventional methotrexate therapy were enrolled. Seventeen patients had polyarticular-onset pJIA; two had oligoarticular-onset pJIA. Mean age was 11.6 years; mean disease duration 5.3 years. American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70, and 90 response rates, respectively, were 94.7%, 94.7%, 57.9%, and 10.5% at week 12, and 100%, 94.1%, 88.2%, and 64.7% at week 48. Mean disease activity score (DAS28) remained below the remission level (2.6) from week 24. Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient (one patient) and antitocilizumab antibodies developed (one patient). Adverse events were generally mild, and the four serious adverse events resolved spontaneously or with treatment. In conclusion, tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA, which suggests that it is a promising new treatment for this disease.
This study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in patients with active systemic juvenile idiopathic arthritis (sJIA) who have an inadequate clinical response to NSAIDs and corticosteroids. In Part I of the study patients will be randomized 2:1 to receive iv infusions of RoActemra/Actemra (8mg/kg iv for patients \>=30kg, or 12mg/kg for patients \<30kg) or placebo, every 2 weeks. Stable NSAIDs and methotrexate will be continued throughout. After 12 weeks of double-blind treatment, all patients will have the option to enter Part II of the study to receive open-label treatment with RoActemra/Actemra for a further 92 weeks, followed by a 3-year continuation of the study in Part III in which, for patients who meet specific criteria, an optional alternative dosing schedule decreasing the study drug administration frequency will be introduced. Anticipated time on study treatment is up to 5 years.
ANTECEDENTES: inicio sistémico de la artritis idiopática juvenil no siempre responden a los tratamientos disponibles, incluidos los agentes del factor de necrosis antitumoral. Hemos investigado la eficacia y seguridad de tocilizumab, un anticuerpo monoclonal anti-interleucina-6-receptor, en los niños con este trastorno.
Métodos: 56 niños (de 2-19 años) con enfermedad refractaria al tratamiento convencional recibieron tres dosis de tocilizumab 8 mg / kg cada 2 semanas durante una de 6 semanas de etiqueta abierta de plomo en fase. Pacientes que alcanzaron un Colegio Americano de Reumatología Pediátrica (ACR Pedi) 30 respuesta y una concentración de proteína C-reactiva (CRP) de menos de 5 mg / L fueron asignados al azar para recibir placebo o continuar el tratamiento con tocilizumab durante 12 semanas o hasta la retirada para el rescate medicamentos en una fase doble ciego. El criterio principal de valoración de la fase de doble ciego fue una respuesta ACR Pedi 30 concentración de la respuesta y la CRP de menos de 15 mg / L. Los pacientes que respondieron a tocilizumab y que necesitan tratamiento adicional se inscribieron en una fase de extensión abierta durante al menos 48 semanas. El análisis se realizó por intención de tratar. Este estudio se ha registrado en ClinicalTrials.gov, número NCT00144599 (para el abierto de lead-in y fases doble ciego) y NCT00144612 (para la fase de extensión abierta).
RESULTADOS: Al final de la fase de plomo-en-etiqueta abierta, ACR Pedi 30, 50, y 70 respuestas se lograron por 51 (91%), 48 (86%), y 38 (68%) pacientes, respectivamente. 43 pacientes continuaron la fase doble ciego y se incluyeron en el análisis de eficacia. Cuatro (17%) de 23 pacientes en el grupo de placebo mantiene una respuesta ACR Pedi 30 y una concentración de PCR de menos de 15 mg / l en comparación con 16 (80%) de 20 en el grupo de tocilizumab (p <0,0001). En la semana 48 de la fase abierta de extensión, ACR Pedi 30, 50, y 70 se lograron 47 (98%), 45 (94%), y 43 (90%) de 48 pacientes, respectivamente. Los eventos adversos graves fueron reacción anafiláctica, hemorragia gastrointestinal, bronquitis y gastroenteritis.
INTERPRETACIÓN: El tocilizumab es eficaz en niños con artritis idiopática juvenil sistémica aparición. Por lo tanto, podría ser un tratamiento adecuado en el control de este trastorno, que ha sido hasta ahora difícil de manejar.
Eighteen Caucasian (white, Middle East and Asian) children diagnosed by paediatric rheumatologists in the UK and France as having systemic juvenile idiopathic arthritis (sJIA) were enrolled in this open label, single dose trial. All patients had evidence of continued symptoms and disease activity for at least three months while receiving >0.2 mg/kg/day of prednisolone, or its equivalent, prior to recruitment. Twelve patients also received methotrexate (< or =20 mg/m2/week). The patients were divided into three groups receiving 2, 4 or 8 mg/kg of MRA (tocilizumab) by intravenous infusion. No evidence of dose-limiting toxicity was observed and there were no dose-limiting safety issues. MRA appeared to be dramatically effective, with clinical and laboratory responses observed by 48 h post infusion, and these improvements continued well after serum MRA was undetectable. Eleven patients achieved the JIA definition of improvement (at least 3 of 6 core set criteria with a 30% improvement and no more than one worsened by 30%) and eight achieved > or =50% improvement. There were no observable differences with age. Clinical improvement in these children was observed for up to eight weeks, supporting the hypothesis that IL-6 is a key cytokine in the upregulation of genes crucial in the inflammation processes of sJIA, and the possibility of sequestration of MRA in the extra-vascular compartment needs to be considered.
OBJECTIVE: To investigate the safety and efficacy of a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody (MRA) that indirectly inhibits the effects of IL-6 in children with systemic-onset juvenile idiopathic arthritis (JIA) refractory to high-dose, long-term corticosteroids.
METHODS: An individual escalating-dose trial was conducted in 11 children with active systemic-onset JIA who met the inclusion criteria. All were first administered an intravenous dose of 2 mg/kg MRA. Each child without active inflammation was given a second identical dose 2 weeks later and a third identical dose 2 weeks after the second dose. Children with disease flares according to laboratory marker values received a 4-mg/kg dose. Those without disease flares at this dose received a second 4-mg/kg dose 2 weeks later and a third 4-mg/kg dose 2 weeks after the second dose, while those with active inflammation received an additional 3 doses of 8 mg/kg MRA. Efficacy was evaluated every 2 weeks according to responses on the JIA core set of improvement criteria and the results of laboratory tests.
RESULTS: MRA abruptly reduced disease activity in 10 of the 11 children, as assessed by the occurrence of febrile episodes, active arthritis, scores on the Childhood Health Assessment Questionnaire, and levels of acute-phase reactants. However, levels of inflammatory reactants fluctuated until the proper MRA dose for each child was reached. Two weeks after the third fixed dose of MRA, 90.9% of all patients had a 30% improvement response, 90.9% had a 50% improvement response, and 63.6% had a 70% improvement response.
CONCLUSION: MRA treatment of children with active systemic disease results in clinical improvement and in normalized levels of acute-phase reactants. MRA was safe and well tolerated and provided greater clinical benefit than conventional corticosteroids, considering the ill effects of IL-6 and adverse events.
We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis (pJIA) with polyarticular or oligoarticular onset. Patients received 8 mg/kg tocilizumab every 4 weeks in the open-label studies: initial study (to week 12) and then an extension study (at least 48 weeks). Nineteen patients intractable to conventional methotrexate therapy were enrolled. Seventeen patients had polyarticular-onset pJIA; two had oligoarticular-onset pJIA. Mean age was 11.6 years; mean disease duration 5.3 years. American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70, and 90 response rates, respectively, were 94.7%, 94.7%, 57.9%, and 10.5% at week 12, and 100%, 94.1%, 88.2%, and 64.7% at week 48. Mean disease activity score (DAS28) remained below the remission level (2.6) from week 24. Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient (one patient) and antitocilizumab antibodies developed (one patient). Adverse events were generally mild, and the four serious adverse events resolved spontaneously or with treatment. In conclusion, tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA, which suggests that it is a promising new treatment for this disease.
