BACKGROUND: Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent changes, disease course, and pharmacokinetic processes paediatric patients with inflammatory rheumatic diseases (PiRD) differ from adult rheumatology patients.
METHODS: A systematic literature search for randomized clinical trials (RCTs) in PiRD treated with bDMARDs/JAK inhibitors was conducted on Medline, clinicaltrials.gov , clinicaltrialsregister.eu and conference abstracts as of July 2020. RCTs were included if (i) patients were aged ≤20 years, (ii) patients had a predefined rheumatic diagnosis and (iii) RCT reported predefined outcomes. Selected studies were excluded in case of (i) observational or single arm study or (ii) sample size ≤5 patients. Study characteristics were extracted.
RESULTS: Out of 608 screened references, 65 references were selected, reporting 35 unique RCTs. All 35 RCTs reported efficacy while 34/3 provided safety outcomes and 16/35 provided pharmacokinetic data. The most common investigated treatments were TNF inhibitors (60%), IL-1 inhibitors (17%) and IL-6 inhibitors (9%). No RCTs with published results were identified for baricitinib, brodalumab, certolizumab pegol, guselkumab, risankizumab, rituximab, sarilumab, secukinumab, tildrakizumab, or upadacitinib. In patients with juvenile idiopathic arthritis (JIA) 25/35 RCTs were conducted. The remaining 10 RCTs were performed in non-JIA patients including plaque psoriasis, Kawasaki Disease, systemic lupus erythematosus and non-infectious uveitis. In JIA-RCTs, the control arm was mainly placebo and the concomitant treatments were either methotrexate, non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids. Non-JIA patients mostly received NSAID. There are ongoing trials investigating abatacept, adalimumab, baricitinib, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, risankizumab, secukinumab, tofacitinib and tildrakizumab.
CONCLUSION: Despite the FDA Modernization Act and support of major paediatric rheumatology networks, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO), which resulted in drug approval for PiRD indications, there are limited RCTs in PiRD patients. As therapy response is influenced by age-dependent changes, pharmacokinetic processes and disease course it is important to consider developmental changes in bDMARDs/JAK inhibitor use in PiRD patients. As such it is critical to collaborate and conduct international RCTs to appropriately investigate and characterize efficacy, safety and pharmacokinetics of bDMARDs/JAK inhibitors in paediatric rheumatology.
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.
BACKGROUND AND OBJECTIVE: Although various biological agents are in use for polyarticular juvenile idiopathic arthritis (pJIA), head-to-head trials comparing the efficacy and safety among them are lacking. We aimed to compare the efficacy and safety of biological agents in pJIA using all currently available randomized withdrawal trials (wRCTs).
METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov was performed. Eligible wRCTs: patients with pJIA where a biological agent was compared with another biological agent or placebo. Efficacy was evaluated using disease flare as a measure. Adverse events (AEs) and serious AEs were evaluated. Network meta-analysis compared biological agents based on a (empirical Bayes) mixed-effects logistic regression model that combines statistical inference from both direct and indirect comparisons of the treatment effects between biological agents.
RESULTS: Of 496 references identified, five wRCTs were included-abatacept, adalimumab, anakinra, etanercept, and tocilizumab, one trial each, all vs. placebo. There were no differences in efficacy among biological agents and most showed statistically significant efficacy compared with placebo (nearly all exceptions were in agreement with the original study data). Serious AEs occurred very infrequently (0-8%) and an analysis was not possible. There were no differences for AEs when compared among biological agents or to placebo.
CONCLUSION: There were no statistical differences among biological agents for efficacy or safety. Overall, biological agents were effective and safe when compared to placebo. Based on these data, other considerations such as price and availability may need to be used to decide among biological agents when treating pJIA patients.
Antecedentes: La artritis idiopática juvenil (JIA) se caracteriza por dolor en las articulaciones, hinchazón y una limitación del movimiento causada por la inflamación. El daño conjunto posterior puede conducir a discapacidad y restricción del crecimiento. El tratamiento incluye comúnmente fármacos antirreumáticos modificadores de la enfermedad (DMARD), como el metotrexato. La práctica clínica ahora favorece los nuevos fármacos denominados DMARDs biológicos donde se indica. OBJETIVO: Evaluar la efectividad clínica y costo-efectividad de cuatro DMARDs biológicos [etanercept (Enbrel®, Pfizer), abatacept (Orencia®, Bristol-Myers Squibb), adalimumab (Humira®, AbbVie) y tocilizumab (RoActemra®, Roche) - con o sin metotrexato cuando se indique] para el tratamiento de la JIA (excluye la JIA sistémica o oligoarticular). FUENTES DE DATOS: Se buscaron bases de datos bibliográficas electrónicas que incluyeron MEDLINE, EMBASE, The Cochrane Library y la Base de Datos de Resúmenes de Reseñas de Efectos desde el inicio hasta mayo de 2015 para artículos en inglés. Bibliografías de artículos relacionados, revisiones sistemáticas y presentaciones de empresas fueron seleccionados y se contactó a expertos para identificar pruebas adicionales. MÉTODOS DE REVISIÓN: Se realizaron revisiones sistemáticas de la efectividad clínica, la calidad de vida relacionada con la salud y la relación costo-efectividad, de acuerdo con la declaración de los Informes Preferidos para Revisiones Sistemáticas y Meta-Análisis. Se desarrolló un modelo analítico-de-decisión de costo-utilidad para comparar la rentabilidad estimada de los FARM biológicos versus el metotrexato. El horizonte temporal del caso base fue de 30 años y el modelo adoptó una perspectiva del NHS, con costos y beneficios descontados en un 3,5%. Resultados: Cuatro ensayos controlados aleatorios (ECA) controlados con placebo cumplieron los criterios de inclusión para la revisión de la eficacia clínica (un ECA evaluó cada DMARD biológico). Sólo un ECA incluyó participantes del Reino Unido. Los participantes tuvieron que lograr una respuesta del American College of Rheumatology Pediatric (ACR Pedi) -30 al tratamiento de entrada abierta con el fin de ser asignados al azar. Una comparación indirecta ajustada exploratoria sugiere que los cuatro FARM biológicos son similares, con menos brotes de enfermedad y mayores proporciones de respuestas ACR Pedi-50 y -70 entre los participantes asignados al azar a DMARDs biológicos continuados. Sin embargo, los intervalos de confianza fueron amplios, el número de ensayos fue bajo y hubo heterogeneidad clínica entre los ensayos. Las extensiones abiertas de los ensayos mostraron que, en general, las respuestas de ACR permanecieron constantes o incluso aumentaron después de la fase doble ciego. Las proporciones de eventos adversos y eventos adversos graves fueron generalmente similares entre los grupos de tratamiento y de placebo. Se identificaron cuatro evaluaciones económicas de DMAR biológicas para pacientes con JIA pero todas tenían limitaciones. Se incluyeron dos estudios de calidad de vida, uno de los cuales informó al modelo de costo-utilidad. Las relaciones incrementales costo-efectividad (ICERs) para adalimumab, etanercept y tocilizumab versus metotrexato fueron £ 38.127, £ 32.526 y £ 38.656 por año de vida ajustado a la calidad (QALY), respectivamente. El ICER para abatacept versus metotrexato como segunda línea biológica fue £ 39.536 por QALY. LIMITACIONES: El modelo no incorpora la historia natural de JIA en términos de progresión a largo plazo de la enfermedad, ya que la evidencia actual es limitada. No hay pruebas de cabeza a cabeza de DMARDs biológicas, y la evidencia clínica para subtipos específicos de JIA es limitada. CONCLUSIONES: Los DMARDs biológicos son superiores al placebo (con metotrexato cuando se permite) en niños con JIA (predominantemente) poliarticular JIA que han tenido una respuesta insuficiente al tratamiento previo. Las comparaciones aleatorizadas de DMARDs biológicos con seguimiento a largo plazo de eficacia y seguridad son necesarias para establecer la eficacia comparativa. Los ECA para los subtipos de la AIJ de los que no se dispone de pruebas son también necesarios. REGISTRO DEL ESTUDIO: Este estudio está registrado como PROSPERO CRD42015016459. FINANCIAMIENTO: El Instituto Nacional de Investigación en Salud programa de Evaluación de Tecnologías de la Salud.
Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent changes, disease course, and pharmacokinetic processes paediatric patients with inflammatory rheumatic diseases (PiRD) differ from adult rheumatology patients.
METHODS:
A systematic literature search for randomized clinical trials (RCTs) in PiRD treated with bDMARDs/JAK inhibitors was conducted on Medline, clinicaltrials.gov , clinicaltrialsregister.eu and conference abstracts as of July 2020. RCTs were included if (i) patients were aged ≤20 years, (ii) patients had a predefined rheumatic diagnosis and (iii) RCT reported predefined outcomes. Selected studies were excluded in case of (i) observational or single arm study or (ii) sample size ≤5 patients. Study characteristics were extracted.
RESULTS:
Out of 608 screened references, 65 references were selected, reporting 35 unique RCTs. All 35 RCTs reported efficacy while 34/3 provided safety outcomes and 16/35 provided pharmacokinetic data. The most common investigated treatments were TNF inhibitors (60%), IL-1 inhibitors (17%) and IL-6 inhibitors (9%). No RCTs with published results were identified for baricitinib, brodalumab, certolizumab pegol, guselkumab, risankizumab, rituximab, sarilumab, secukinumab, tildrakizumab, or upadacitinib. In patients with juvenile idiopathic arthritis (JIA) 25/35 RCTs were conducted. The remaining 10 RCTs were performed in non-JIA patients including plaque psoriasis, Kawasaki Disease, systemic lupus erythematosus and non-infectious uveitis. In JIA-RCTs, the control arm was mainly placebo and the concomitant treatments were either methotrexate, non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids. Non-JIA patients mostly received NSAID. There are ongoing trials investigating abatacept, adalimumab, baricitinib, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, risankizumab, secukinumab, tofacitinib and tildrakizumab.
CONCLUSION:
Despite the FDA Modernization Act and support of major paediatric rheumatology networks, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO), which resulted in drug approval for PiRD indications, there are limited RCTs in PiRD patients. As therapy response is influenced by age-dependent changes, pharmacokinetic processes and disease course it is important to consider developmental changes in bDMARDs/JAK inhibitor use in PiRD patients. As such it is critical to collaborate and conduct international RCTs to appropriately investigate and characterize efficacy, safety and pharmacokinetics of bDMARDs/JAK inhibitors in paediatric rheumatology.
