OBJECTIVE: The clinical impact of anti-drug antibodies (ADAbs) in paediatric patients with JIA remains unknown. This systematic review and meta-analysis aimed to summarize the prevalence of ADAbs in JIA studies; investigate the effect of ADAbs on treatment efficacy and adverse events; and explore the effect of immunosuppressive therapy on antibody formation.
METHODS: PubMed, Embase and the Cochrane Library were systematically searched to identify relevant clinical trials and observational studies that reported prevalence of ADAbs. Studies were systematically reviewed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses and appropriate proportional and pairwise meta-analyses were performed.
RESULTS: A total of 5183 references were screened; 28 articles, involving 26 studies and 2354 JIA patients, met eligibility criteria. Prevalence of ADAbs ranged from 0% to 82% across nine biologic agents. Overall pooled prevalence of ADAbs was 16.9% (95% CI, 9.5, 25.9). Qualitative analysis of included studies indicated that antibodies to infliximab, adalimumab, anakinra and tocilizumab were associated with treatment failure and/or hypersensitivity reactions. Concomitant MTX uniformly reduced the risk of antibody formation during adalimumab treatment (risk ratio 0.33; 95% CI 0.21, 0.52).
CONCLUSION: The association of ADAbs with treatment failure and hypersensitivity reactions indicates their clinical relevance in paediatric patients with JIA. Based on our findings, we recommend a preliminary course of action regarding immunogenicity of biologic agents in patients with JIA. Further strategies to predict, prevent, detect and manage immunogenicity could optimize treatment outcomes and personalize treatment with biologic therapies.
Objectives: Treatment of juvenile idiopathic arthritis has changed rapidly since the introduction of various biologics almost twenty years ago. Many clinical trials have been performed to monitor efficacy and safety of new agents. The aim of this review is to summarize safety concerns, which were observed during prospective clinical trials. Methods: Since etanercept was the first biologic approved and remains the most frequently used, as first biologic in polyarticular JIA patients, the authors calculated the relative risk of the adverse events for all examined biologicals and compared the values with the value of etanercept. Results: Relative rates for all adverse events showed similar rates for etanercept, infliximab, golimumab and tocilizumab, whereas adalimumab showed higher rates and abatacept lower rates. Comparison of rates for serious adverse events demonstrated, that rates seemed comparable for etanercept, adalimumab, infliximab and tocilizumab. Again, abatacept showed a lower rate, whereas golimumab seems to have a higher relative risk for serious adverse events. Rate of infection was lowest in patients treated with abatacept or tocilizumab, patients treated with etanercept, adalimumab and Infliximab again had similar rates. Conclusion: The safety profiles of actually approved biologics are highly acceptable. However further observation, especially long-term observation through registry studies, is required.
ANTECEDENTES: La represión de la cascada inmunoinflamatorio apuntando a la interleucina 6 (IL-6) los efectos mediados constituye una opción terapéutica para las enfermedades inflamatorias crónicas. Tocilizumab es la IL-6 solo inhibidor (IL-6i) con licencia para la artritis reumatoide (AR) y artritis idiopática juvenil (AIJ), sino también otros agentes dirigidos a cualquiera de IL-6 o de su receptor se investigó en varias indicaciones.
OBJETIVO: Revisar la evidencia publicada sobre la seguridad y eficacia de la IL-6i en las enfermedades inflamatorias.
MÉTODOS: Se realizó búsquedas sistemáticas de la literatura en Medline y Cochrane, Colegio blindado EULAR y Americano de Reumatología reunión-resúmenes, y se accede a http://www.clinicaltrials.gov.
RESULTADOS: La evidencia Integral apoya la eficacia de tocilizumab en la AR en pacientes sin tratamiento previo con FARME, y después de FAME y TNFi de fallos. Comparaciones aleatorias demostrar la superioridad de tocilizumab en la AIJ, pero no la espondilitis anquilosante (AS). Otras indicaciones son actualmente investigados. Adicional IL-6i espectáculo similar eficacia, la seguridad aparece generalmente aceptable.
Conclusiones: IL-6i es eficaz y seguro en la AR y AIJ, pero no en AS. Los resultados preliminares en otras indicaciones necesita justificación.
OBJETIVO: Evaluar la farmacología, la eficacia clínica, la seguridad, y el papel de tocilizumab para el tratamiento de la artritis idiopática juvenil.
FUENTES DE DATOS: Una búsqueda en la literatura a través de MEDLINE a través de PubMed (1970-diciembre de 2011) y International Pharmaceutical Abstracts (1970-Diciembre 2011) se llevó a cabo para identificar los ensayos clínicos y artículos de revisión. Los términos clave de búsqueda tocilizumab, anti-interleuquina 6 y juvenil se utilizaron artritis idiopática, con varias combinaciones de términos. Se examinaron las bibliografías de los artículos seleccionados para identificar referencias adicionales, y se identificaron ensayos en curso mediante un examen de www.clinicaltrials.gov.
SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: Los artículos se limitan a los publicados en Inglés y estudios en humanos. Los estudios incluidos en la revisión examinaron datos pediátricos en la artritis idiopática juvenil sistémica y poliarticular. La información de antecedentes se obtuvo a través de revisiones de la literatura en una amplia variedad de enfermedades autoinmunes, tanto en poblaciones adultas y pediátricas.
SÍNTESIS: El tocilizumab es aprobado por la Administración de Alimentos y Medicamentos para su uso en pacientes de 2 años con artritis idiopática juvenil sistémica. Tocilizumab fue superior al placebo en el desencadenamiento de una respuesta sintomática durante la Fase 2 y 3 de ensayos clínicos. Tocilizumab se determinó que era seguro, con sólo un pequeño número de eventos adversos por medicamentos grave que se produzca dentro de los estudios.
CONCLUSIONES: El tocilizumab ofrece expansión de las opciones disponibles para el tratamiento de la artritis idiopática juvenil sistémica, específicamente en pacientes que no han respondido a las terapias convencionales. Tocilizumab es relativamente bien tolerado y ha demostrado su eficacia durante un máximo de 52 semanas. Se necesitan más estudios para determinar su utilidad como una opción de primera línea para la artritis idiopática juvenil sistémica, así como su papel en el tratamiento de la artritis idiopática juvenil poliarticular.
The clinical impact of anti-drug antibodies (ADAbs) in paediatric patients with JIA remains unknown. This systematic review and meta-analysis aimed to summarize the prevalence of ADAbs in JIA studies; investigate the effect of ADAbs on treatment efficacy and adverse events; and explore the effect of immunosuppressive therapy on antibody formation.
METHODS:
PubMed, Embase and the Cochrane Library were systematically searched to identify relevant clinical trials and observational studies that reported prevalence of ADAbs. Studies were systematically reviewed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses and appropriate proportional and pairwise meta-analyses were performed.
RESULTS:
A total of 5183 references were screened; 28 articles, involving 26 studies and 2354 JIA patients, met eligibility criteria. Prevalence of ADAbs ranged from 0% to 82% across nine biologic agents. Overall pooled prevalence of ADAbs was 16.9% (95% CI, 9.5, 25.9). Qualitative analysis of included studies indicated that antibodies to infliximab, adalimumab, anakinra and tocilizumab were associated with treatment failure and/or hypersensitivity reactions. Concomitant MTX uniformly reduced the risk of antibody formation during adalimumab treatment (risk ratio 0.33; 95% CI 0.21, 0.52).
CONCLUSION:
The association of ADAbs with treatment failure and hypersensitivity reactions indicates their clinical relevance in paediatric patients with JIA. Based on our findings, we recommend a preliminary course of action regarding immunogenicity of biologic agents in patients with JIA. Further strategies to predict, prevent, detect and manage immunogenicity could optimize treatment outcomes and personalize treatment with biologic therapies.
