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Novel algorithm identifies adverse drug events across the seven pediatric development stages

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Side effects from pediatric drug treatment are responsible for nearly 10 percent of childhood hospitalizations, with nearly half of those being life-threatening. Despite the need to know more about these drugs and the adverse events they can have on children, little evidence is currently available.

Clinical trials remain the gold standard for identifying adverse drug events (ADEs) for adults, but these have both ethical and methodological concerns for the pediatric population. The rapidly changing biologic and physiologic developments only enhance the challenges of understanding the potential impacts of different drug treatments at various stages of childhood.

Researchers at the Columbia University Irving Medical Center developed a novel algorithm that identified nearly 20,000 ADEs signals (information on a new or known side effect that may be caused by a particular drug) across the seven pediatric development stages and made them freely available. This process is strengthened by a novel approach that allows neighboring development stages to enhance the signal detection power, which helps it overcome limited data within individual stages.

This use of predictive modeling on real-world data can help address a critical gap in healthcare research around the understudied pediatric community.

DBMI associate professor Nicholas Tatonetti and Nick Giangreco, a recent Systems Biology PhD graduate at Columbia University, shared these findings in the study A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development, which was recently published in Med.

For many reasons, children have historically not been included in clinical trials. There are many ethical issues around including children in trials, and there are several limitations when children are included that make it difficult to assess the effectiveness and safety of drugs.”

Nicholas Tatonetti, DBMI associate professor

Because of these factors, few drugs are specifically approved for use in children, though once drugs are approved for adults, physicians can prescribe them “off-label” to children.

“Since drugs are not studied and approved in children directly, physicians must rely on guidelines for adults,” he added. “Essentially treating children as if they were simply small adults is oftentimes an incorrect assumption. This study is an attempt to elucidate systematically what the potential side effects are when drugs are used off label in children.”

The study goes beyond simply differentiating side effects in children from those in adults. It focuses on ADEs across seven developmental stages, starting at term neonatal and going through late adolescence, and it is powered by sharing information from neighboring developmental stages. For example, the development of infants and toddlers is close enough that there will be more shared characteristics than there would be for infants and those in early or late adolescence.

“Previously, children were essentially grouped together,” Tatonetti said. “There were only a few studies that just focused on children, and they basically focused on people 18 and under or 21 and under in one group. The innovation here is using known developmental stages and our newly introduced DGAMs (disproportionality generalized additive models) to improve power and enable that analysis.”

Tatonetti stressed that these signals are not validated and are primarily meant for researchers. Parents should consult with their pediatricians on specific drug side effects.

Giangreco, currently a Quantitative Translational Scientist at Regeneron, noted one of several side effects that were identified by this model.

“One we corroborated that the FDA had found was that montelukast, an asthma drug, was found to elicit psychiatric side effects,” he said. “We saw that in our database as well, but we were able to pinpoint certain developmental stages where the risk was more significant, especially the second year of life.”

The study also integrates pediatric enzyme expression data and found that pharmacogenes with dynamic childhood expression are associated with pediatric ADEs.

“This was a biologically-inspired modeling strategy,” Giangreco said. “We used what we knew about biological processes occurring during childhood and formed the modeling strategy. These safety signals came from this prior knowledge of the biological processes that are happening. Our data-driven approach really tried to capture what we thought were the important biologically and physiologically dynamic processes that happen during childhood and use that to tease apart observations across the development stages.”

The model was used on a database of 264,453 pediatric reports in the FDA Adverse Event Reporting System (FAERS). The output of the study is available via KidSIDES, a free and publicly available database of pediatric drug safety signals for the research community, as well as the Pediatric Drug Safety portal (PDSportal), which will facilitate evaluation of drug safety signals across childhood growth and development.

“The primary intention is for other researchers to use it, to follow up on signals they may observe,” Tatonetti said. “If they are experts on a particular drug usage, or particular disease domain and have observed these types of effects, they could follow up on them and be reassured, or could look at what the other evidence is for that effect as we aggregate it together. Clinicians can use it as a gut check. Maybe they saw an effect, or they are wondering if others are seeing this effect, and they can check the PDSPortal to see if others are seeing this effect or to prompt them to write another case report to the FDA.”

Source:

Journal reference:

Giangreco, N.P., et al. (2022) A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development. Med. doi.org/10.1016/j.medj.2022.06.001.

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Study identifies an epigenetic regulator that suppresses pathogenic events in rheumatoid arthritis

Study identifies an epigenetic regulator that suppresses pathogenic events in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by chronic inflammation of synovium, eventually leading to joint destruction. Epigenetic alteration (the mechanism of gene expression regulation without DNA sequence changes), such as low levels of DNA methylation, is one of the factors which worsens the RA state. However the mechanism by which the alterations occur remains largely unknown.

In the present study, we identified an epigenetic regulator UHRF1 that was remarkably up-regulated in synovial fibroblasts (SF) from arthritis model mice and RA patients. Previous study showed that UHRF1 is a key player in the maintenance of DNA methylation, although the function for RA is unknown. To understand UHRF1 function for arthritis, we generated mice with SF-specific UHRF1 conditional knockout (cKO) and experimental arthritis was induced.

cKO mice exhibited more severe arthritic phenotypes than the littermate control. Next, to reveal UHRF1 function in SF, RNA-seq and MBD-seq were performed using SF obtained from the control and cKO mice. Integrative genome-wide analyses of the transcriptome and methylome showed that expression of several cytokines was up-regulated in UHRF1-deficient SF accompanied by reduced DNA methylation signatures.

Also, UHRF1 expression in synovium was negatively correlated with several pathogenesis in RA patients. These data suggested that RA pathogenesis is exacerbated when UHRF1 levels are low in SF. Finally, we assessed whether UHRF1 stabilization contributes to improvement of arthritis pathogenesis. Ryuvidine, which was identified as a candidate chemical compound to the stabilize UHRF1 protein, was administrated in arthritis model mice.

The results showed that arthritis pathogenesis was ameliorated by treatment with Ryuvidine. Also, the development of organoids derived from RA-SF was suppressed by Ryuvidine.

This study demonstrated that UHRF1 expressed in SF with RA has a protective role in suppressing multiple pathogenic events in arthritis, suggesting that targeting UHRF1 could be a therapeutic strategy for RA.

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Study Identifies 24 Adverse Events Associated with Secukinumab Treatment

Study Identifies 24 Adverse Events Associated with Secukinumab Treatment

A new systematic review of secukinumab-induced adverse events of special interest (AESI) in patients with moderate to severe plaque psoriasis found that the most common AESI were inflammatory bowel disease, eczematous drug eruption, drug-associated vasculitis, and drug-induced lupus erythematosus.

Despite most AESI being deemed mild to moderately severe in nature, these types of events have been increasingly reported in real-world practice.

Additionally, the adverse effect profile of the treatment has not been fully described in previous research, and many of the adverse effects such as lupus erythematosus had not been identified in clinical trials despite gradually being reported in more case reports and case series.

As such, an investigative team led by Jingyao Liang, PhD, Institute of Dermatology at Guangzhou Medical University, China, perfomed a systematic review intended to establish a secukinumab-induced AESI profile and management strategies.

The literature search was performed in PubMed databases from the earliest cases of secukinumab use to August 2021 for the treatment of any type of clinical condition.

Search terms such as secukinumab or secukinumab-induced, adverse effects, side effects, and adverse events were used to find relevant studies, at which point investigators extracted data regarding study type, demographics, treatment history and dosage, disease type, onset of AESI, and management and outcomes of AESI.

Overall, the search resulted in 1426 potentially relevant articles, 55 of which were included in the review. Among these studies were 2 clinical studies, 2 reviews, 50 case reports, and 1 case series, all of which were published between 2016 and 2021.

Investigators noted that more thab 1077 adult patients 18-74 years old experienced AESi after being treated with secukinumab for a myriad of conditions including psoriatic disease and spondyloarthritis (SpA).

The onset of the AESI ranged from 2 days to 96 weeks, and a total of 24 AESI were identified, including adiposity, alopecia areata, bullous eruption, scleroderma, and the AESI previously listed.

The most commonly reported AESI was IBD with over 1000 cases, followed by eczematous drug eruptions at 30 cases and drug-associated vasculitis at 8 cases.

As mentioned, most of the events were mild to moderate in severity, and patients typically experienced full recovery following discontinuation. Notably, some patients continued secukinumab treatment due to significant disease regression, with AESI being stabilized and/or well-controlled by other treatments.

With this study, investigators suggested that clinicians “should be aware that secukinumab may cause various AESI and follow-up patients for exacerbation of symptoms or new onset of AESI during treatment”.

The study, “Review of secukinumab-induced adverse events of special interest and its potential pathogenesis,” was published online in Dermatologic Therapy.