Variants in the gene leading to the protein interleukin-1 receptor antagonist (or IL1RA) do not seem to affect the response of children with systemic juvenile idiopathic arthritis (sJIA) to the approved IL-1 blocking therapies Kineret (anakinra) and Ilaris (canakinumab), a new study reports.
However, those who receive treatment later in the disease course are more likely to have poorer long-term response to therapy, “supporting the ‘window of opportunity’ hypothesis,” the researchers said.
Their study, “Impact of IL1RN variants on response to interleukin‐1 blocking therapy in systemic juvenile idiopathic arthritis,” was published in the journal Arthritis & Rheumatology.
sJIA is caused by deregulation of the immune system and increased production of pro-inflammatory signals, including IL-1 and IL-6.
While corticosteroids have been the standard treatment for this young population, three biological therapies have recently been approved in Europe for the treatment of sJIA.
Sobi’s Kineret and Novartis’ Ilaris are designed to specifically block the pro-inflammatory signals driven by IL-1, while Genentech’s Actemra (tocilizumab) is intended to prevent binding of IL-6 to its receptor. In the U.S., Ilaris and Actemra, but not Kineret, have been approved to treat sJIA.
Despite the beneficial effect of these therapies, response to IL-1 blockade varies greatly among affected children.
Researchers in Germany evaluated if high levels of IL1RA — a naturally occurring protein that suppresses IL-1 receptor signals and was used as a model to design Kineret — could be involved in poor responses to IL-1 blocking therapy.
They conducted a genetic analysis of children with sJIA who participated in the German Autoinflammatory Disease registry. The team determined the presence of genetic variants of the gene coding for IL1RA, known as IL1RN, which could induce overproduction of the protein. The researchers analyzed six of seven variants that were previously associated with response to Kineret.
Among a total of 61 children (median 5.2 years at disease onset), 93.4% were treated with Kineret, 24.6% with Ilaris, and 18% with both. Overall, 67% of them showed at least a transient clinical response, while 26% had a poor response.
Results showed no association between IL1RN variants and response to any of the evaluated IL-1 blocking therapies — as determined by outcome measures including physician global assessments and the modified Juvenile Arthritis Disease Activity Score.
A previous study had failed to find a link between IL1RN variants and the risk for sJIA in German patients, which was in contrast to several other studies in different populations.
“Therefore, it is possible that genetic risk factors for sJIA and for treatment non-response vary in different populations,” the researchers suggested.
Analysis of blood biomarkers revealed that IL-1RA levels were different between the two response groups, as they were higher in children who responded to treatment than in those who did not. However, these increased levels are most likely due to Kineret (an engineered form of IL-1RA) itself, as it was used by many of the children when their blood samples were collected, according to the researchers.
The data also showed that children who received Actemra following IL-1 blockade had a longer duration between disease onset and diagnosis, as well as higher levels of inflammatory markers, than those who did not.
“We could not confirm an impact of IL1RN [variants] on response to therapy with anakinra [Kineret] or canakinumab [Ilaris] in a cohort of patients with SJIA,” the researchers wrote.
However, the children’s clinical records revealed that those diagnosed earlier (closer to disease onset) were more likely to respond to IL-1 blocking therapy and not require a switch to Actemra.
“There is evidence for a ‘window of opportunity’ in this cohort, [in other words] improved long-term treatment response with shorter time from disease onset to diagnosis,” the team said.
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