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.
Purpose Significant numbers of children and teenagers with COVID-19 have developed a severe inflammatory condition with a Kawasaki-like disease. Some needed intensive care unit admission, and others recovered quickly. We aimed to summarize the clinical and laboratory features of patients with Kawasaki-like features diagnosed during the COVID-19 pandemic. Methods A literature search in Web of Science, PubMed, Scopus, and Science Direct up to June 30, 2020. The mean or untransformed proportion and 95%CI were estimated. Results Analysis of 15 articles (318 COVID-19 patients) revealed that the mean age was 9.10 years. Although many presented with typical Kawasaki-like features; fever (82.4%), polymorphous maculopapular exanthema (63.7%), oral mucosal changes (58.1%), conjunctival injections (56.0%), edematous extremities (40.7%), and cervical lymphadenopathy (28.5%), atypical gastrointestinal (79.4%) and neurocognitive symptoms (31.8%) were also common. They had elevated LDH, D-dimer, CRP, procalcitonin, interleukin-6, troponin I levels, and lymphopenia. Nearly 77.0% developed hypotension, and 68.1% went into shock, while 41.1% had acute kidney injury. Intensive care was needed in 73.7% of cases, 13.2% were intubated, and 37.9% required mechanical ventilation, with only one reported fatality case. Intravenous immunoglobulins and steroids were given in 87.7% and 56.9% of the patients, and anticoagulants were utilized in 67.0%. Pediatric patients were discharged after a hospital stay of, on average, 6.77 days (95%CI:4.93-8.6). Conclusion Recognizing the typical and atypical presentation of pediatric COVID-19 patients has important implications in identifying children at risk. Monitoring cardiac and renal decompensation and early interventions in patients with “multisystem inflammatory syndrome” is critical to prevent further morbidity.
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.
OBJETIVO: Definir el agente biológico óptimo para la AIJ sistémica (AIJ), basado en los datos de seguridad y eficacia de un ensayo controlado aleatorio (ECA).
MÉTODOS: A través de una búsqueda sistemática de la literatura, se identificaron ECA que evalúan sJIA agentes biológicos. El criterio principal de eficacia fue definida como una mejora del 30% de acuerdo con el Colegio Americano de Reumatología pediátrica modificado 30 criterios de respuesta (AIJ ACR30). La variable principal de seguridad se definió como eventos adversos graves (AAG). Los resultados se analizaron por pares y de la red metanálisis. La calidad de las pruebas entre los agentes biológicos se evaluó mediante la aplicación de la clasificación de las recomendaciones de la evaluación, la metodología de Desarrollo y Evaluación (GRADE).
RESULTADOS: De las 493 citas identificadas inicialmente, 5 ECA fueron elegibles para su inclusión-uno para la anakinra, canakinumab y tocilizumab y dos para rilonacept: todo frente a placebo. Aunque todos eran eficaces, la red de meta-análisis indicó con la evidencia de baja calidad (debido a la comparación indirecta e inconsistencia) que los pacientes rilonacept tratadas eran menos propensos a responder que los tratados con canakinumab [odds ratio (OR) 0,10 (95% CI 0,02, 0,38), p = 0,001] o tocilizumab [OR 0,12 (IC del 95%: 0,03, 0,44), p = 0,001]. Los riesgos de eventos adversos graves fueron similares entre los agentes biológicos (apoyados por pruebas muy baja calidad) y no diferente del placebo.
CONCLUSIÓN: A pesar de los criterios de elegibilidad heterogéneos y diseños de estudio en los cinco estudios y diferentes criterios ACR30 AIJ modificados, este meta-análisis de ECA a corto plazo presenta evidencia empírica de que canakinumab y tocilizumab son más eficaces que rilonacept. Los agentes biológicos en la AIJ sistémica parecen seguros y comparables con respecto al riesgo de SAE en el corto plazo.
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.
