Genetic Signature May Identify sJIA Children Who Respond to Ilaris

Genetic Signature May Identify sJIA Children Who Respond to Ilaris
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A specific genetic signature can help in identifying children with systemic onset juvenile arthritis (sJIA) who are most likely to respond well to Ilaris (canakinumab), a study suggests.

Children with a more severe dysregulation of genes associated with signaling cascades involved in the control of immune and inflammatory responses were likely to have strong responses to treatment, the scientists found. But further studies are needed to confirm these observations so they might be of clinical use.

The study, “Distinct gene expression signatures characterize strong clinical responders vs non‐responders to Canakinumab in children with sJIA,” was published in the journal Arthritis & Rheumatology and was conducted by .

sJIA is characterized by widespread tissue inflammation, driven mainly by excessive production of pro-inflammatory molecules such as interleukin-1 (IL-1) and interleukin-6 (IL-6).

Ilaris, developed by Novartis, is approved in the U.S. and Europe to treat children with sJIA, ages 2 and older. The medication works by blocking the activity of interleukin-1 beta (IL-1β), a protein that helps to control the immune response and that is known to cause inflammation at excessive levels.

“While many patients have dramatic clinical response to IL‐1 blockade, approximately one‐third fail to respond, but there currently exist no validated clinical or immunologic predictors of response,” the researchers wrote.

A team led by researchers at Cincinnati Children’s Hospital Medical Center, in Ohio, analyzed the genetic profile of children with sJIA who responded poorly to Ilaris and compared it those who responded well to the medication. Their intent was to identify a specific gene signature that might serve to predict response.

Their study focused on re-analyzing data on whole blood gene expression (activity) gathered during two Novartis-sponsored Phase 3 trials (NCT00886769 and NCT00889863) of Ilaris’ safety and efficacy in children with sJIA.

Data covered 86 sJIA children and 22 healthy children as controls. Among patients, these data included gene expression both before treatment start (baseline measures) and on the third day after beginning treatment with Ilaris.

Children with sJIA were also divided into two groups, depending on their treatment responses according to criteria set by the American College of Rheumatology (ACR). Stronger responders were defined as patients with an improvement greater than 90% in at least three of the six ACR core criteria, and without worsening of over 30% in more than one criterion. Patients were considered non-responders if they attained an improvement of 30% or less in at least three of the six ACR core criteria, while worsening more than 30% in another ACR criterion.

The six ACR core criteria are fatigue, joint pain, morning stiffness, soft tissue swelling, joint tenderness or pain in motion, and a measure of inflammation.

In agreement with previous studies, investigators found that strong responders had a higher number of dysregulated genes before starting treatment (9,629), compared with non-responders (6,017).

After analyzing patients’ gene expression signature at baseline in more detail, strong responders were found to have a set of overactive genes associated with immune cell activation, and involved in the control of pro-inflammatory signaling pathways (e.g., IL-1 signaling).This genetic signature, however, reverted to a nearly normal pattern — similar to that observed in controls — once strong responders had started using Ilaris.“Non-responders presented with a much more modest change of gene expression, which is barely affected by canakinumab [Ilaris] treatment,” the investigators wrote.

They also found that a particular gene in non-responders, called CD163, was overly active prior to treatment and continued to be active after starting on Ilaris. This gene is normally active in a subset of regulatory immune cells, and its activity is usually driven by the anti-inflammatory molecule interleukin-10.

“Taken together, our findings highlight a role for severe dysregulation of pro-inflammatory genes and immune pathways that present a target for canakinumab in canakinumab responders,” the researchers wrote.

“However, our findings are limited by the lack of a suitable independent validation [group], and thus further studies are required to validate and define this profile for prospective utility in a clinical setting,” they added.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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