BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease affecting both adults and children. To better understand the efficacy-safety profile of biologics in children with moderate-to-severe psoriasis, this study aimed to analyze efficacy and safety data of randomized controlled trials (RCTs) performed in pediatric psoriasis and to compare efficacy outcomes in children with those in adults.
METHODS: RCTs investigating biologics in children with moderate-to-severe psoriasis were identified in a systematic literature review. PASI75/90 treatment responses at weeks 11/12 were analyzed comparing biologics with control arms. Serious adverse events (SAEs) were analyzed at the end of each study. Efficacy data from RCTs in adults with psoriasis were selected for the same biologics. Risk ratios (RR) of selected RCTs were pooled together in a statistical random effects model using the inverse variance method.
RESULTS: For children, there were 1 etanercept, 2 secukinumab, 1 ixekizumab and 1 ustekinumab placebo-controlled RCTs and 1 adalimumab RCT using methotrexate as reference arm at weeks 11/12. For adults, out of 263 RCTs, 7 adalimumab and 15 etanercept (TNF inhibitors) and 4 ixekizumab and 12 ustekinumab (IL-17 and IL-12/23 inhibitors) RCTs reported PASI75/90 efficacy responses at weeks 11/12. Regarding efficacy, all biologics showed improved PASI responses over control arms. RRs ranges were 2.02-7.45 in PASI75 and 4.10-14.50 in PASI90. The highest PASI75 responses were seen for ustekinumab 0.375 mg/kg (RR = 7.25, 95% CI 2.83-18.58) and ustekinumab 0.75 mg/kg (RR = 7.45, 95% CI 2.91-19.06) in the CADMUS study. The highest PASI90 response was seen for ixekizumab (RR = 14.50, 95% CI 4.82-43.58) in the IXORA-PEDS study. SAE incidences in pediatric and adult arms with biologics were 0 to 3% except for a pediatric arm with adalimumab 0.40 mg/kg (8%). For adults, pooled RR also showed improved PASI responses over placebo for all biologics, with highest PASI75 response observed for ixekizumab (pooled RR = 16.18, 95% CI 11.83-22.14).
CONCLUSION: Both adults and children with psoriasis show superior efficacy with biologics compared to control arms after 3 months of treatment with SAE incidences in the low percentages. Additional longer-term clinical studies are warranted to fully understand the overall efficacy-safety profile of biologics in children with moderate-to-severe psoriasis.
BACKGROUND: Biologics represent a promising treatment for children with moderate-to-severe psoriasis. Randomized control trials (RCTs) have been published evaluating different biologics in children with psoriasis, but no summative review exists.
OBJECTIVE: To summarize data from existing RCTs to assess the efficacy and safety of biologics in the management of pediatric psoriasis.
METHODS: A systematic review and meta-analysis of RCTs was performed from Medline, Embase, PubMed, the Cochrane Central Register of Controlled Trials, and the American College of Physicians Journal Club from inception to November 2020. Random-effects models were used to estimate the pooled effect size.
RESULTS: Five RCTs assessing adalimumab, etanercept, ixekizumab, secukinumab, and ustekinumab were included (768 patients). The odds ratio of achieving a 75% improvement in Psoriasis Area and Severity index score was 12.37 (95% CI: 6.23-24.55) at initial follow-up, defined as 12-16 weeks of treatment. The odds ratio of any adverse event was 0.95 (95% CI: 0.51-1.80) at initial follow-up, in patients treated with biologics when compared to placebo or a non-biologic agent. Limitations of this study include heterogeneity in both the study design and the biologics investigated between the RCTs included in the meta-analysis.
CONCLUSION: Biologic therapy for pediatric patients with moderate-to-severe psoriasis has high efficacy and a favorable side effect profile.
Background: Psoriasis is a chronic, immune-mediated skin disease that may occur at any age. Prevalence in children ranges between 0.5 and 1.0% across Europe. Approximately 10-20% of paediatric psoriasis patients are moderate-to-severe in severity and may require the use of systemic therapy. Objective: Recently, newer targeted, systemic therapies have been licensed for treatment of moderate-to-severe paediatric psoriasis. The objective of this study was to evaluate the short-term efficacy of available antipsoriatic systemic drugs in children with a narrative synthesis of key efficacy from randomized clinical trials. Methods: A systematic review of literature was performed on Medline and embase databases and the Cochrane Central Register of Controlled Trials. Randomized clinical trials investigating the efficacy of treatments licensed by the US Food and Drug Administration and/or the European Medicines Agency for paediatric and adolescent psoriatic population were retrieved and analyzed. Data from this literature review was assessed in line with GRADE (grading of recommendations, assessment, development and evaluations). The short-term (12-16 weeks) clinical efficacy from baseline was evaluated according to the Psoriasis Area and Severity Index (PASI) 75 and 90 compared to baseline. Illustrative comparative risks, relative risk (RR) and the number needed to treat (NNT) for response on PASI 75 and PASI 90 were extracted. Results: A total of five relevant studies were identified on two TNF-alpha blockers (etanercept and adalimumab), the IL12/23 inhibitor ustekinumab and two IL-17 inhibitors (ixekizumab, secukinumab). Comparators were placebo (3 studies), placebo and etanercept (1 study) methotrexate (1 study). All examined drugs resulted efficacious. The probability to achieve PASI 75 and PASI 90 was higher for the IL-12/23 and IL-17 inhibitors. Overall, the anti-IL17s and the anti-IL12/23 antibodies showed a more favourable NNT for PASI 75, whereas IL-17 inhibitors for PASI 90. Conclusion: The approved biological therapies may be beneficial for the treatment of moderate to severe plaque psoriasis in children and adolescents. Since psoriasis is a chronic and often challenging condition with no definitive solution, systematic evaluations of long-term efficacy, drug survival and adverse effects may help careful, individualized, patient-centered clinical decision making.
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.
Psoriasis is a chronic immune-mediated skin disorder. Due to lack of clarity in its pathogenesis, a cure with existing treatment is a big challenge. Biologics, a revolutionary treatment, are potent immunomodulators that explicitly target the culprit cells of the immune system to achieve the maximum level of Psoriasis Area and Severity Index (PASI) score (75 to 90) and clear or almost clear skin in moderate to severe psoriasis. They have been a successful therapy in adult severe psoriasis for a decade. In recent years, biologics have unprecedently sought the attention of the pediatric psoriatic population by proving an efficacious and safe option. The aim of the study is to provide a systematic review of efficacy, safety, and impact on the quality of life of Food and Drug Administration (FDA)-approved biologics, namely etanercept and ustekinumab, and their use as a "first-line systemic therapy" in the moderate to severe pediatric and adolescent psoriatic population. We explored PubMed, Cochrane Library, Google Scholar, American Academy of Dermatology website, ClinicalTrials.gov, the FDA site, and the National Psoriasis Foundation USA site as major database searches. Psoriasis, pediatric, etanercept, and ustekinumab were keywords used to find the relevant literature. Clinical trials and observational studies were retrieved and analyzed to assess the efficacy and safety of FDA-approved biologics as first-line systemic therapy in pediatric psoriasis. The relevant evidence-based studies and the Joint American Academy of Dermatology-National Psoriasis Foundation (AAD-NPF) guideline have shown that etanercept and ustekinumab biologics are significantly effective and safe systemic therapies in dealing with moderate to severe psoriasis in pediatric and adolescent patients and have unprecedently improved their quality of life. Thus, they can be confidently considered as first-line systemic therapy in moderate to severe pediatric and adolescent psoriatic patients by applying the specific criteria and proper monitoring. However, health practitioners and dermatologists must educate pediatric patients and their caretakers about their adverse effects, success/failure chance, careful monitoring, and follow-up plan to achieve the desired result.
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.
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: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA(®), AbbVie, Maidenhead, UK), etanercept (Enbrel(®), Pfizer, New York, NY, USA) and ustekinumab (STELARA(®), Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children.
OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people.
DATA SOURCES: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation.
REVIEW METHODS: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway.
RESULTS: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks' follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE's usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted.
LIMITATIONS: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children.
CONCLUSIONS: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities.
STUDY REGISTRATION: This study is registered as PROSPERO CRD42016039494.
FUNDING: The National Institute for Health Research Health Technology Assessment programme.
Varios tratamientos biológicos están autorizados para la psoriasis. La falta de ensayos controlados aleatorios cabeza a cabeza (ECA) hace que la elección entre ellos sea difícil para los pacientes, los clínicos y los desarrolladores de la guía. Para establecer su eficacia y tolerabilidad relativa, se realizaron búsquedas en MEDLINE, PubMed, Embase y Cochrane para ECA de tratamientos biológicos con licencia para la psoriasis de la piel. Se realizó un meta-análisis de la red para identificar la evidencia directa e indirecta que comparaba los productos biológicos entre sí, el metotrexato o el placebo. Combinamos esto con el análisis de agrupamiento jerárquico para considerar múltiples resultados relacionados con la eficacia y tolerabilidad en combinación para cada tratamiento. Se evaluó la calidad del estudio, la heterogeneidad y la inconsistencia. Se incluyeron comparaciones directas de 41 ECA (20.561 participantes). Todos los productos biológicos incluidos fueron eficaces en comparación con placebo o metotrexato a los 3-4 meses. En general, el análisis de conglomerados mostró que adalimumab, secukinumab y ustekinumab eran comparables en términos de alta eficacia y tolerabilidad. Ixekizumab e infliximab se diferenciaron por una eficacia muy alta pero una tolerabilidad más baja. La falta de datos controlados a más largo plazo limitó nuestro análisis a resultados a corto plazo. El desempeño del ensayo puede no equipararse al desempeño del mundo real, por lo que los resultados deben considerarse junto con los datos de seguridad y efectividad a largo plazo del mundo real. Estos datos sugieren que es posible discriminar entre los biológicos para informar la práctica clínica y la toma de decisiones. PROSPERO 2015: CRD42015017538.
Psoriasis is a chronic immune-mediated inflammatory skin disease affecting both adults and children. To better understand the efficacy-safety profile of biologics in children with moderate-to-severe psoriasis, this study aimed to analyze efficacy and safety data of randomized controlled trials (RCTs) performed in pediatric psoriasis and to compare efficacy outcomes in children with those in adults.
METHODS:
RCTs investigating biologics in children with moderate-to-severe psoriasis were identified in a systematic literature review. PASI75/90 treatment responses at weeks 11/12 were analyzed comparing biologics with control arms. Serious adverse events (SAEs) were analyzed at the end of each study. Efficacy data from RCTs in adults with psoriasis were selected for the same biologics. Risk ratios (RR) of selected RCTs were pooled together in a statistical random effects model using the inverse variance method.
RESULTS:
For children, there were 1 etanercept, 2 secukinumab, 1 ixekizumab and 1 ustekinumab placebo-controlled RCTs and 1 adalimumab RCT using methotrexate as reference arm at weeks 11/12. For adults, out of 263 RCTs, 7 adalimumab and 15 etanercept (TNF inhibitors) and 4 ixekizumab and 12 ustekinumab (IL-17 and IL-12/23 inhibitors) RCTs reported PASI75/90 efficacy responses at weeks 11/12. Regarding efficacy, all biologics showed improved PASI responses over control arms. RRs ranges were 2.02-7.45 in PASI75 and 4.10-14.50 in PASI90. The highest PASI75 responses were seen for ustekinumab 0.375 mg/kg (RR = 7.25, 95% CI 2.83-18.58) and ustekinumab 0.75 mg/kg (RR = 7.45, 95% CI 2.91-19.06) in the CADMUS study. The highest PASI90 response was seen for ixekizumab (RR = 14.50, 95% CI 4.82-43.58) in the IXORA-PEDS study. SAE incidences in pediatric and adult arms with biologics were 0 to 3% except for a pediatric arm with adalimumab 0.40 mg/kg (8%). For adults, pooled RR also showed improved PASI responses over placebo for all biologics, with highest PASI75 response observed for ixekizumab (pooled RR = 16.18, 95% CI 11.83-22.14).
CONCLUSION:
Both adults and children with psoriasis show superior efficacy with biologics compared to control arms after 3 months of treatment with SAE incidences in the low percentages. Additional longer-term clinical studies are warranted to fully understand the overall efficacy-safety profile of biologics in children with moderate-to-severe psoriasis.
