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The molecular mechanisms of steroid resistance suggest the P13K/Akt signaling pathway and the MAPK signaling pathway are involved.
While steroid-resistance asthma is a phenotype of severe asthma, the mechanisms of steroid resistance involving type 2 inflammation is not entirely understood.
However, benralizumab could help reduce oral steroid dosage in patients with severe asthma.
A team, led by Keita Hirai, assessed the expression levels of genes involved in the mechanism of steroid resistance and investigated the relationships between the changes in gene expression and lung function, in patients undergoing benralizumab treatment in a study presented at the European Respiratory Society International Congress 2020 (ERS 2020).
Benralizumab is an anti-interleukin 5 receptor α monoclonal antibody that has shown the ability to allow reduced oral steroid dosage in patients with severe asthma, suggesting that the treatment could modify the function of molecules involved in the steroid response.
The molecular mechanisms of steroid resistance suggest the P13K/Akt signaling pathway and the MAPK signaling pathway are involved. In the activation process of the P13K pathway, miR-21 is suggested to play a role in regulating the expression of PTEN, an endogenous inhibitor of P13K.
In the study, all patients were administered 30 mg benralizumab at baseline, as well as weeks 4, 8, 16, and 24. The researchers collected blood samples prior to the administration of treatment until week 24.
They also separated T cells immediately from whole blood and extracted their total RNA.
The study included a total of 17 patients with severe asthma.
The researchers found mRNA expression levels of histone deacetylase 2 (HDAC2), nuclear factor, erythroid 2 like 2 (Nrf2), glucocorticoid induced 1 (GLCCI1), and phosphatase and tensin homolog (PTEN), involved in the phosphoinositide 3-kinase pathway, increased at week 8.
These trends also significantly increased at week 16 and 24 (at week 24; HDAC2, P = 0.011; Nrf2, P = 0.015; GLCCI1, P = 0.020; PTEN, P = 0.027).
They also found changes in expression levels of HDAC2, Nrf2, and GLCCI1 from baseline to week 24 correlated significantly with changes FEV1(HDAC2, r = 0.67; Nrf2, r = 0.62; GLCCI1, r = 0.67), but not PTEN.
“We demonstrated that changes in expression levels of genes involved in steroid resistance were associated with increased FEV1 after benralizumab treatment,” the authors wrote. “Our results may help to understand the pathophysiology of severe asthma.”
In a separate study presented at ERS 2020 determined if and how an add-on treatment with benralizumab could improve the quality of life of patients with severe eosinophilic asthma.
The researchers found both a significant reduction in eosinophilic inflammation, exacerbations, and gaining in pre-bronchodilator FEV1 and symptoms control, with all the enrolled subjects experiencing an improvement in AQLQ [from 3.65±0.56 (baseline) to 4.61±0.67 (12 weeks) (P = 0.003) and to 5.17±0.87 (24 weeks) (P = 0.0002)].
This covered all 4 health domains—symptoms perception, activity limitation, emotional function, and environmental stimuli—investigated (P <0.05).
The study, “Benralizumab restored expression of key molecules involved in steroid-resistance in patients with severe asthma,” was published online by ERS 2020.