Assuntos
Fármacos Dermatológicos , Esclerodermia Localizada , Ustekinumab , Humanos , Ustekinumab/efeitos adversos , Ustekinumab/uso terapêutico , Esclerodermia Localizada/induzido quimicamente , Esclerodermia Localizada/patologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Feminino , Psoríase/tratamento farmacológico , Pessoa de Meia-Idade , MasculinoRESUMO
BACKGROUND: Biological therapies are effective for psoriasis, but patient responses vary, often requiring therapy switching or discontinuation. OBJECTIVES: To identify physicians' prescribing patterns of biological therapies at a referral tertiary center in Saudi Arabia and assess the probability of biologic persistence following treatment initiation. METHODS: We conducted a retrospective study of biologic-naïve adult psoriasis patients who initiated therapy from October 2013 to July 2022 in Dammam. Descriptive statistics and a Kaplan-Meier analysis evaluated treatment persistence at 6, 12, 24, and 36 months. RESULTS: A total of 151 patients received adalimumab (n = 89), etanercept (n = 17), risankizumab (n = 30), ustekinumab (n = 14), and ixekizumab (n = 1). At 6 months, all therapies demonstrated 100% persistence. At 12 months, persistence was highest for ustekinumab (100%) and lowest for etanercept (88.2%). At 24 months, ustekinumab maintained 100% persistence, followed by risankizumab (96.6%), adalimumab (94.3%), and etanercept (76.4%). At 36 months, risankizumab had the highest persistence (96.6%), followed by adalimumab (83.1%), ustekinumab (78%), and etanercept (70.6%). The most common reasons for discontinuation were lack of effectiveness and intolerability. CONCLUSION: This study shows changing psoriasis treatment patterns with new therapies. Risankizumab demonstrated high long-term persistence, while etanercept and ustekinumab showed declining persistence, suggesting evolving treatment considerations.
Assuntos
Adalimumab , Etanercepte , Padrões de Prática Médica , Psoríase , Ustekinumab , Humanos , Psoríase/tratamento farmacológico , Estudos Retrospectivos , Arábia Saudita , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Padrões de Prática Médica/estatística & dados numéricos , Ustekinumab/uso terapêutico , Etanercepte/uso terapêutico , Adalimumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Anticorpos Monoclonais/uso terapêutico , Terapia BiológicaRESUMO
Seven of the 11 newer medications recently or soon to be approved to treat rheumatologic diseases discussed in this article are biologic agents and reflect the current ability of science to target specific components of the immune system. The other agents are molecules that are directed against specific immune pathway targets as well. All have shown superiority to placebo and in some cases have been compared to currently accepted therapies. Safety issues are generally centered around infections due to the immune-interrupting nature of these therapies.
Assuntos
Antirreumáticos , Doenças Reumáticas , Humanos , Doenças Reumáticas/tratamento farmacológico , Antirreumáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Abatacepte/uso terapêutico , Rituximab/uso terapêutico , Adalimumab/uso terapêutico , Etanercepte/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Reumatologia/métodos , Ustekinumab/uso terapêutico , Proteínas Recombinantes de FusãoRESUMO
BACKGROUND: The efficacy and safety of risankizumab as compared with ustekinumab in patients with Crohn's disease are unknown. METHODS: In this phase 3b, multicenter, open-label, randomized, controlled trial with blinded assessment of end points, patients with moderate-to-severe Crohn's disease who had had an inadequate response to anti-tumor necrosis factor (TNF) therapy or unacceptable side effects with such therapy were randomly assigned to receive risankizumab or ustekinumab at standard doses for 48 weeks. The two primary end points, which were tested sequentially, were clinical remission at week 24 (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]), which was analyzed in the first 50% of patients to complete the week 24 visit, with a noninferiority margin of 10 percentage points; and endoscopic remission at week 48 (defined as a score of ≤4, a decrease of ≥2 points from baseline, and no subscore >1 in any individual variable on the Simple Endoscopic Score for Crohn's Disease [range, 0 to 56, with higher scores indicating more severe disease]), which was analyzed for superiority in 100% of the patients. Safety was assessed in all patients who received at least one dose of risankizumab or ustekinumab. RESULTS: In the full intention-to-treat population for the efficacy analysis, 230 of 255 patients (90.2%) who received risankizumab and 193 of 265 patients (72.8%) who received ustekinumab completed all the assigned treatments. Both primary end points were met; risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 (58.6% vs. 39.5%; adjusted difference, 18.4 percentage points; 95% confidence interval [CI], 6.6 to 30.3) and superior to ustekinumab with respect to endoscopic remission at week 48 (31.8% vs. 16.2%; adjusted difference, 15.6 percentage points; 95% CI, 8.4 to 22.9; P<0.001). The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: In this head-to-head clinical trial of risankizumab and ustekinumab involving patients with moderate-to-severe Crohn's disease who had had unacceptable side effects with anti-TNF therapy or an inadequate response to such therapy, risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 and superior with respect to endoscopic remission at week 48. (Funded by AbbVie; ClinicalTrials.gov number, NCT04524611.).
Assuntos
Anticorpos Monoclonais , Doença de Crohn , Indução de Remissão , Ustekinumab , Humanos , Doença de Crohn/tratamento farmacológico , Ustekinumab/uso terapêutico , Ustekinumab/efeitos adversos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Índice de Gravidade de Doença , Análise de Intenção de Tratamento , Adulto JovemAssuntos
Psoríase , Esclerodermia Localizada , Ustekinumab , Humanos , Ustekinumab/uso terapêutico , Ustekinumab/efeitos adversos , Psoríase/tratamento farmacológico , Esclerodermia Localizada/tratamento farmacológico , Esclerodermia Localizada/diagnóstico , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Resultado do TratamentoRESUMO
The modern treatment of inflammatory bowel disease (IBD) has evolved significantly in recent years. This includes development of new pharmacologic therapies and their implementation in clinical practice. Moderate-to-severe IBD represents a group of patients at risk of poorer outcomes, and mounting evidence suggests biologic and small molecule medications, collectively termed advanced therapies, are the most effective tools clinicians possess. Even with biologic treatment, many patients do not respond or lose response over time. Until recently, most randomised trials demonstrating efficacy and safety of biologics have been placebo-controlled with a lack of head-to-head studies. Therefore, selecting the right medication for the appropriate clinical scenario can be difficult. In addition, there is evidence of differing clinical success when positioning biologic treatments in different sequences. This is important, as one-third of patients treated with biologics will require a switch to a second agent by 12 months, and a further 20% will require a third agent. Over the years, there have been widespread calls in Aotearoa New Zealand for increasing biologic treatment options. Ustekinumab and vedolizumab received public funding for the treatment of moderate-to-severe IBD in 2023, and this has presented long-awaited opportunities for patients, but also new challenges for clinicians in regard to treatment selection. The purpose of this document is to provide guidance to clinicians on biologic selection, sequencing and optimisation for IBD. These recommendations are specific to the domestic prescribing climate, supported by the best available evidence and endorsed by the New Zealand Society of Gastroenterology IBD Working Group.
Assuntos
Doenças Inflamatórias Intestinais , Humanos , Nova Zelândia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Ustekinumab/uso terapêuticoRESUMO
Ustekinumab has been shown to be effective in inducing and maintain clinical and endoscopic remission in Crohn disease (CD). We aim to assess whether ustekinumab trough levels are associated with improved outcomes in CD in real-life. We recruited patients with CD who were treated with ustekinumab for at least 6 months from January 2017 to June 2023. Patients received ustekinumab 6 mg/kg intravenous induction followed by 90 mg every 4-, 8-, or 12-weeks during maintenance were included. We assessed clinical, biochemical, and endoscopic outcomes. Trough concentrations of ustekinumab that were taken from week 42 to week 52 were measured. Primary outcome was to evaluate the relationship between ustekinumab trough concentrations and clinical remission, biochemical normalization, and endoscopic remission. Logistic regression was conducted to assess outcomes. A total of 137 patients with CD, median age of 32 years and 83 (60.6%) males. The median serum levels of ustekinumab measured was 7.2 mcg/mL (interquartile range [IQR] 3.1-9.6). Using Spearman correlation analysis, a strong negative correlation was observed between ustekinumab drug levels and simple endoscopic score (SES-CD) (râ =â -0.464, Pâ <â .001). Additionally, ustekinumab drug levels demonstrated substantial negative correlations with disease severity measured by Harvey-Bradshaw index (HBI) score (râ =â -0.582, Pâ <â .001), C-Reactive Protein (CRP) levels (râ =â -0.598, Pâ <â .001) and fecal calprotectin (FC) levels (râ =â -0.529, Pâ <â .001). A multivariable analysis adjusted for age, sex and body mass index (BMI) showed a significant association between ustekinumab serum drug levels and predefined outcomes. Ustekinumab serum drug level above 4.5 mcg/mL was associated with 24% increase in the likelihood of having an SES-CD score <3 (OR 1.24, confidence interval [CI] 1.12-1.37, P valueâ <â .001), 44% more likely to achieve HBI score <5 (OR 1.44, CI 1.26-1.65, P valueâ <â .001), 52% higher likelihood of CRP more than 10 (OR 1.52, CI 1.31-1.77, Pâ <â .001), and 42% increased likelihood of FC more than 250 (OR 1.42, CI 1.24-1.62, Pâ <â .001). Ustekinumab trough concentrations above 4.5 mcg/mL were associated with clinical, biochemical and endoscopic remission in CD. Prospective data is warranted to confirm these findings.
Assuntos
Doença de Crohn , Ustekinumab , Humanos , Ustekinumab/uso terapêutico , Ustekinumab/farmacocinética , Doença de Crohn/tratamento farmacológico , Doença de Crohn/sangue , Masculino , Feminino , Adulto , Estudos Retrospectivos , Indução de Remissão/métodos , Resultado do Tratamento , Pessoa de Meia-Idade , Proteína C-Reativa/análiseAssuntos
Medicamentos Biossimilares , Ustekinumab , Humanos , Medicamentos Biossimilares/uso terapêutico , Medicamentos Biossimilares/efeitos adversos , Ustekinumab/uso terapêutico , Psoríase/tratamento farmacológico , Estados Unidos , Fármacos Dermatológicos/uso terapêutico , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Fármacos Dermatológicos/administração & dosagem , Aprovação de Drogas , United States Food and Drug AdministrationRESUMO
BACKGROUND: Although biologic agents are very effective, long-term comparative studies demonstrating their safety relative to one another are still lacking. METHODS: A total of 124 patients with psoriasis were followed up for 30 months; 74 received anti-TNF-alpha inhibitors (adalimumab, etanercept, infliximab), 33 were on ustekinumab, and 17 were treated with secukinumab. The rates of adverse events in these groups were recorded and statistically analyzed. RESULTS: Infliximab-treated patients showed a high occurrence of asymptomatic, but increased liver enzymes, fatigue, and respiratory as well as dermatologic infections. Adalimumab-treated patients were more often affected by musculoskeletal disorders and infections of all types. Patients treated with secukinumab presented with higher rates of cardiovascular disorders as well as respiratory and dermatologic infections. The group receiving etanercept was more often diagnosed with musculoskeletal and reproductive disorders, specifically menstrual disorders. The rates of therapy discontinuation and serious adverse events did not reach statistically significant values. CONCLUSION: A higher incidence of adverse events was observed among adalimumab-, and infliximab-treated patients, with ustekinumab found to have the safest profile. Our results demonstrate that a personalized approach, including evaluation of a patient's risk profile, is necessary before commencing a biologic. Further research is warranted to confirm the findings of our study.
Assuntos
Adalimumab , Anticorpos Monoclonais Humanizados , Etanercepte , Infliximab , Psoríase , Ustekinumab , Humanos , Psoríase/tratamento farmacológico , Feminino , Masculino , Ustekinumab/uso terapêutico , Ustekinumab/efeitos adversos , Estudos Prospectivos , Adalimumab/efeitos adversos , Adalimumab/uso terapêutico , Infliximab/efeitos adversos , Infliximab/uso terapêutico , Pessoa de Meia-Idade , Adulto , Etanercepte/efeitos adversos , Etanercepte/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Estudos de Coortes , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêuticoRESUMO
Ustekinumab and vedolizumab are key treatment options for Crohn's disease patients who fail anti-tumor necrosis factor (TNF) therapy. This updated meta-analysis aims to compare the efficacy and safety of these two drugs. We performed a systematic review in PubMed, Embase , and Cochrane databases searching for randomized and nonrandomized studies comparing vedolizumab versus ustekinumab in patients with Crohn's disease with previous anti-TNF failure or intolerance. The primary outcome was steroid-free clinical remission (SFR) at the pos-induction (12-16 weeks) and maintenance period (48-52 weeks). The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I2 statistics. This meta-analysis included 11 studies and 2724 patients. There was a significant difference favoring ustekinumab in SFR at pos-induction (OR, 1.44; 95% CI, 1.11-1.88; P â =â 0.006; I2 â =â 27%) and maintenance periods (OR, 1.86; 95% CI, 1.23-2.82; P â =â 0.003; I2 â =â 80%), in clinical remission at pos-induction period (OR, 2.04; 95% CI, 1.58-2.63; P â <â 0.001; I2 â =â 3%), and in treatment discontinuation due to adverse events (OR, 0.31; 95% CI, 0.16-0.60; P â <â 0.001; I2 â =â 0%). In patients with Crohn's disease with prior anti-TNF failure, ustekinumab showed higher SFR during both the pos-induction and maintenance period and a lower rate of treatment discontinuation due to adverse events.
Assuntos
Anticorpos Monoclonais Humanizados , Doença de Crohn , Fármacos Gastrointestinais , Indução de Remissão , Ustekinumab , Doença de Crohn/tratamento farmacológico , Ustekinumab/uso terapêutico , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Fármacos Gastrointestinais/efeitos adversos , Falha de Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Resultado do Tratamento , Razão de ChancesRESUMO
AVT04 (Uzpruvo®) is a biosimilar of the reference anti-interleukin (IL)-12 and IL-23 monoclonal antibody ustekinumab. It is approved in the EU for plaque psoriasis, paediatric plaque psoriasis, psoriatic arthritis and Crohn's disease as per the reference product. AVT04 has similar physicochemical characteristics to those of reference ustekinumab, and the pharmacokinetic similarity of the agents has been shown in healthy volunteers and patients with moderate to severe chronic plaque psoriasis. AVT04 demonstrated clinical efficacy similar to that of reference ustekinumab in patients with moderate to severe chronic plaque psoriasis, and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of AVT04 were similar to those of reference ustekinumab, and switching from reference ustekinumab to AVT04 had no impact on efficacy, safety or immunogenicity. The role of reference ustekinumab in the management of inflammatory diseases is well established and AVT04 provides an effective biosimilar alternative for patients requiring ustekinumab therapy.
Assuntos
Medicamentos Biossimilares , Psoríase , Ustekinumab , Humanos , Ustekinumab/uso terapêutico , Ustekinumab/farmacocinética , Medicamentos Biossimilares/uso terapêutico , Medicamentos Biossimilares/farmacocinética , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacologia , Psoríase/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Fármacos Dermatológicos/farmacocinética , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Doença de Crohn/tratamento farmacológicoRESUMO
BACKGROUND: The present study aimed to dissect the cellular complexity of Crohn's disease (CD) using single-cell RNA sequencing, focusing on identifying key cell populations and their transcriptional profiles in inflamed tissue. METHODS: We applied scRNA-sequencing to compare the cellular composition of CD patients with healthy controls, utilizing Seurat for clustering and annotation. Differential gene expression analysis and protein-protein interaction networks were constructed to identify crucial genes and pathways. RESULTS: Our study identified eight distinct cell types in CD, highlighting crucial fibroblast and T cell interactions. The analysis revealed key cellular communications and identified significant genes and pathways involved in the disease's pathology. The role of fibroblasts was underscored by elevated expression in diseased samples, offering insights into disease mechanisms and potential therapeutic targets, including responses to ustekinumab treatment, thus enriching our understanding of CD at a molecular level. CONCLUSIONS: Our findings highlight the complex cellular and molecular interplay in CD, suggesting new biomarkers and therapeutic targets, offering insights into disease mechanisms and treatment implications.
Assuntos
Doença de Crohn , Análise de Célula Única , Ustekinumab , Doença de Crohn/genética , Doença de Crohn/tratamento farmacológico , Humanos , Ustekinumab/uso terapêutico , Análise de Célula Única/métodos , Perfilação da Expressão Gênica/métodos , Mapas de Interação de Proteínas , Fibroblastos/metabolismo , Biomarcadores , Feminino , Transcriptoma , Adulto , Masculino , Linfócitos T/metabolismo , Linfócitos T/imunologia , Resultado do Tratamento , Análise de Sequência de RNA/métodos , Redes Reguladoras de GenesRESUMO
Long-term data on ustekinumab in real-life Crohn's disease patients are still missing, though randomized controlled trials demonstrated it as a favorable therapeutic option. We aimed to evaluate ustekinumab's clinical efficacy, drug sustainability, and safety in a prospective, nationwide, multicenter Crohn's disease patient cohort with a three-year follow-up. Crohn's disease patients on ustekinumab treatment were consecutively enrolled from 9 Hungarian Inflammatory Bowel Disease centers between January 2019 and May 2020. Patient and disease characteristics, treatment history, clinical disease activity (Harvey Bradshaw Index (HBI)), biomarkers, and endoscopic activity (Simple Endoscopic Score for Crohn's Disease (SES-CD)) were collected for three-years' time. A total of 148 patients were included with an overall 48.9% of complex behavior of the Crohn's disease and 97.2% of previous anti-TNF exposure. The pre-induction remission rates were 12.2% (HBI), and 5.1% (SES-CD). Clinical remission rates (HBI) were 52.2%, 55.6%, and 50.9%, whereas criteria of an endoscopic remission were fulfilled in 14.3%, 27.5%, and 35.3% of the subjects at the end of the first, second, and third year, respectively. Dose intensification was high with 84.0% of the patients on an 8-weekly and 29.9% on a 4-weekly regimen at the end of year 3. Drug sustainability was 76.9% during the follow-up period with no serious adverse events observed. Ustekinumab in the long-term is an effective, sustainable, and safe therapeutic option for Crohn's disease patients with severe disease phenotype and high previous anti-TNF biological failure, requiring frequent dose intensifications.
Assuntos
Doença de Crohn , Ustekinumab , Humanos , Doença de Crohn/tratamento farmacológico , Ustekinumab/uso terapêutico , Ustekinumab/efeitos adversos , Masculino , Feminino , Adulto , Resultado do Tratamento , Pessoa de Meia-Idade , Estudos Prospectivos , Seguimentos , Indução de Remissão , HungriaRESUMO
INTRODUCTION: Anti-interleukin 12/23 agents have shown greater durability in response compared with anti-tumor necrosis factor α agents. Data on the association between body composition (BC) or body mass index (BMI) and ustekinumab's therapeutic response is limited. We aimed to evaluate the impact of BC on time to failing standard doses of ustekinumab in patients with Crohn's disease (CD). METHOD: Patients with CD aged 16 years and older from 2 tertiary centers were studied retrospectively. Included patients had abdominal imaging within 6 months of ustekinumab induction and were followed until April 30, 2022. An experienced abdominal radiologist blinded to the clinical information measured the area of visceral fat area and skeletal muscle area at the mid L3 vertebral level, with values corrected for height 2 to derive respective indices (visceral fat index [VFI], skeletal muscle index [SMI]) and the VFI:SMI ratio. RESULTS: Ninety-nine patients met inclusion criteria. The mean age at ustekinumab induction was 46.6 (±1.6) years. The median BMI (interquartile range) was 26.5 (22.6-30.8). Twenty-four patients (24.2%) did not respond or lost response to standard doses of ustekinumab over the follow-up duration. A younger age (hazard ratio 0.96, 95% confidence interval 0.94-0.99, P = 0.01) and a VFI:SMI ratio >1.6 (hazard ratio 4.65, 95% confidence interval 1.73-12.45, P = 0.002) were both associated with a shorter time to failing ustekinumab at standard doses on multivariate analysis. BMI, notably, had no association with the primary outcome. DISCUSSION: A high VFI:SMI ratio is associated with an increased risk of failing standard doses of ustekinumab. BC measurements derived from cross-sectional imaging at the start of ustekinumab therapy is a useful indicator for therapeutic durability.
Assuntos
Índice de Massa Corporal , Doença de Crohn , Gordura Intra-Abdominal , Músculo Esquelético , Falha de Tratamento , Ustekinumab , Humanos , Ustekinumab/administração & dosagem , Ustekinumab/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/efeitos dos fármacos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/diagnóstico por imagem , Composição Corporal/efeitos dos fármacos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Variations exist in the response of patients with Crohn's disease (CD) to ustekinumab (UST) treatment, but the underlying cause remains unknown. Our objective was to investigate the involvement of immune cells and identify potential biomarkers that could predict the response to interleukin (IL) 12/23 inhibitors in patients with CD. METHODS: The GSE207022 dataset, which consisted of 54 non-responders and 9 responders to UST in a CD cohort, was analyzed. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the most powerful hub genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performances of these genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to estimate the proportions of immune cell types. These significantly altered genes were subjected to cluster analysis into immune cell-related infiltration. To validate the reliability of the candidates, patients prescribed UST as a first-line biologic in a prospective cohort were included as an independent validation dataset. RESULTS: A total of 99 DEGs were identified in the integrated dataset. GO and KEGG analyses revealed significant enrichment of immune response pathways in patients with CD. Thirteen genes (SOCS3, CD55, KDM5D, IGFBP5, LCN2, SLC15A1, XPNPEP2, HLA-DQA2, HMGCS2, DDX3Y, ITGB2, CDKN2B and HLA-DQA1), which were primarily associated with the response versus nonresponse patients, were identified and included in the LASSO analysis. These genes accurately predicted treatment response, with an area under the curve (AUC) of 0.938. T helper cell type 1 (Th1) cell polarization was comparatively strong in nonresponse individuals. Positive connections were observed between Th1 cells and the LCN2 and KDM5D genes. Furthermore, we employed an independent validation dataset and early experimental verification to validate the LCN2 and KDM5D genes as effective predictive markers. CONCLUSIONS: Th1 cell polarization is an important cause of nonresponse to UST therapy in patients with CD. LCN2 and KDM5D can be used as predictive markers to effectively identify nonresponse patients. TRIAL REGISTRATION: Trial registration number: NCT05542459; Date of registration: 2022-09-14; URL: https://www. CLINICALTRIALS: gov .
Assuntos
Biologia Computacional , Doença de Crohn , RNA Mensageiro , Ustekinumab , Adulto , Feminino , Humanos , Masculino , Análise por Conglomerados , Biologia Computacional/métodos , Doença de Crohn/genética , Doença de Crohn/tratamento farmacológico , Perfilação da Expressão Gênica , Ontologia Genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Estudos Prospectivos , Reprodutibilidade dos Testes , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Transcriptoma/genética , Ustekinumab/uso terapêutico , Ustekinumab/farmacologiaRESUMO
Palhano et al. demonstrate the feasibility of incorporating secukinumab and ustekinumab into the Clinical Protocol and Therapeutic Guidelines for moderate to severe psoriasis in pediatric patients. OBJECTIVE: Therefore, this study aimed to evaluate the impact of secukinumab and ustekinumab against moderate-to-severe plaque psoriasis in a Brazilian pediatric population with access to public healthcare. METHODS: A survey of immunobiological treatments registered for use against pediatric psoriasis at the National Health Surveillance Agency was conducted. These treatments were compared to the list available in the same treatment category in the public health system through the Clinical Protocol and Therapeutic Guidelines for psoriasis. A quantitative analysis of the data of patients treated with immunobiological drugs the previous year in accordance with the Clinical Protocol and Therapeutic Guidelines was performed using data available in the DATASUS portal. RESULTS: The public budget impact scenarios analyzed were comparable to the investment already planned for acquiring the only available drug option. CONCLUSION: The incorporation of two therapeutic options in the Clinical Protocol and Therapeutic Guidelines list for moderate-to-severe pediatric psoriasis was feasible in a horizon of 5 years compared to the investment into the single option available to pediatric patients. These findings can facilitate the local analysis of budgetary impact and discussions on the feasibility of this therapeutic incorporation at the state level. Incorporation of secukinumab and ustekinumab was economically feasible. These drugs are options for those who do not respond to or have contraindications to etanercept.
Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Ustekinumab , Humanos , Psoríase/tratamento farmacológico , Criança , Ustekinumab/uso terapêutico , Brasil , Anticorpos Monoclonais Humanizados/uso terapêutico , Índice de Gravidade de Doença , Fármacos Dermatológicos/uso terapêutico , Adolescente , Guias de Prática Clínica como Assunto , Masculino , FemininoRESUMO
Introduction: Crohn's disease (CD) is a chronic inflammatory disease. Approximately 50% of patients with CD progressed from inflammation to fibrosis. Currently, there are no effective drugs for treating intestinal fibrosis. Biologic therapies for CD such as ustekinumab have benefited patients; however, up to 30% of patients with CD have no response to initial treatment, and the effect of ustekinumab on intestinal fibrosis is still uncertain. Therefore, it is of great significance to explore the predictive factors of ustekinumab treatment response and the effect of ustekinumab on intestinal fibrosis. Materials and methods: Public datasets-GSE207465 (blood samples) and GSE112366 and GSE207022 (intestinal samples)-were downloaded and analyzed individually (unmerged) based on the treatment response. Differentially expressed genes (DEGs) were identified by the "limma" R package and changes in immune cell infiltration were determined by the "CIBERSORT" R package in both blood and intestinal samples at week 0 (before treatment). To find predictive factors of ustekinumab treatment response, the weighted gene co-expression network analysis (WGCNA) R package was used to identify hub genes in GSE112366. Hub genes were then verified in GSE207022, and a prediction model was built by random forest algorithm. Furthermore, fibrosis-related gene changes were analyzed in ileal samples before and after treatment with ustekinumab. Results: (1) Our analysis found that MUC1, DUOX2, LCN2, and PDZK1IP1 were hub genes in GSE112366. GSE207022 revealed that MUC1 (AUC:0.761), LCN2 (AUC:0.79), and PDZK1IP1 (AUC:0.731) were also lower in the response group. Moreover, the random forest model was shown to have strong predictive capabilities in identifying responders (AUC = 0.875). To explore the relationship between intestinal tissue and blood, we found that ITGA4 had lower expression in the intestinal and blood samples of responders. The expression of IL18R1 is also lower in responders' intestines. IL18, the ligand of IL18R1, was also found to have lower expression in the blood samples from responders vs. non-responders. (2) GSE112366 revealed a significant decrease in fibrosis-related module genes (COL4A1, TUBB6, IFITM2, SERPING1, DRAM1, NAMPT, MMP1, ZEB2, ICAM1, PFKFB3, and ACTA2) and fibrosis-related pathways (ECM-receptor interaction and PI3K-AKT pathways) after ustekinumab treatment. Conclusion: MUC1, LCN2, and PDZK1IP1 were identified as hub genes in intestinal samples, with lower expression indicating a positive prediction of ustekinumab treatment response. Moreover, ITGA4 and IL18/IL18R1 may be involved in the treatment response in blood and intestinal samples. Finally, ustekinumab treatment was shown to significantly alter fibrotic genes and pathways.
Assuntos
Doença de Crohn , Fibrose , Ustekinumab , Ustekinumab/uso terapêutico , Humanos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Redes Reguladoras de Genes , Perfilação da Expressão Gênica , Transcriptoma , Resultado do Tratamento , Mapas de Interação de ProteínasRESUMO
Ustekinumab (UST), a fully human immunoglobulin G1 κ monoclonal antibody, exhibiting high affinity for the p40 subunit shared by IL-12 and IL-23, which play key roles in the pathogenesis of inflammatory bowel disease (IBD). By scaling the physiologically-based pharmacokinetic modeling (PBPK) model of UST in adult patients with IBD, we aim to predict effective dosages for UST in pediatric patients, thereby offering a more practical dosing regimen for real-world applications. In this work, a PBPK model for UST in adult patients with IBD has been developed using PK-Sim and Mobi. Advanced ontogeny model has been incorporated to extrapolate the model to pediatric patients. The simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (Cmax) were between 0.79 and 1.73. For children aged 6-18, it is recommended to administer the drug per kilogram of body weight, at the model-recommended dose, to achieve a median AUC similar to that of the adult reference population post-administration. This comprehensive model construction enables us to comprehensively and extensively explore the pharmacokinetic characteristics of UST in pediatric patients of different age groups, providing robust support for clinical applications and personalized drug therapy.
Assuntos
Doenças Inflamatórias Intestinais , Modelos Biológicos , Ustekinumab , Humanos , Ustekinumab/farmacocinética , Ustekinumab/administração & dosagem , Criança , Adolescente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Feminino , Área Sob a Curva , Adulto , Simulação por ComputadorRESUMO
Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause. Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: ⢠Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). ⢠Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: ⢠Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. ⢠Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.