NERANDOMILAST reduced lung inflammation and fibrosis in experimental models of idiopathic inflammatory myopathy–associated interstitial lung disease.
Nerandomilast and Idiopathic Inflammatory Myopathy–Associated Interstitial Lung Disease
Idiopathic inflammatory myopathy–associated interstitial lung disease (IIM-ILD) is an autoimmune condition characterized by progressive lung involvement and limited therapeutic options. The disease often develops alongside inflammatory muscle disorders and can lead to significant pulmonary fibrosis and respiratory impairment.
Researchers investigated whether nerandomilast, a phosphodiesterase 4B inhibitor, could offer therapeutic benefit in this setting. Phosphodiesterase 4B plays a central role in regulating cyclic adenosine monophosphate metabolism in lung tissue, making it a potential target for modulating inflammatory pathways involved in autoimmune lung disease.
Study Model and Design
To evaluate the drug’s effects, investigators developed a preclinical mouse model of IIM-ILD through immunization with skeletal muscle homogenate. Mice received nerandomilast twice daily at doses of 5 mg per kilogram or 12.5 mg per kilogram. A separate group received nintedanib once daily as a positive control. Disease severity and treatment response were evaluated using myositis scores, spleen index measurements, imaging, and histopathological analysis.
Treatment with nerandomilast significantly improved disease indicators in the experimental model. Investigators observed reductions in muscle inflammation, pulmonary fibrosis, and lung inflammation following therapy.
Additional analyses showed that nerandomilast directly affected immune cell activity in lung tissue. The treatment reduced infiltration and proliferation of B cells within the lungs and lowered expression of the activation marker BAFF. The drug also suppressed differentiation of B cells into plasma cells by decreasing key transcription factors and plasma cell markers.
Serological findings supported these results. Investigators reported a reduction in positivity for anti-Jo-1 autoantibodies following treatment with nerandomilast, suggesting an effect on autoimmune activity associated with the disease.
B Cell Signaling Pathways Provide Mechanistic Insight
Further molecular analyses demonstrated that nerandomilast increased intracellular cyclic adenosine monophosphate levels in lung tissue. This change was associated with inhibition of several signaling pathways linked to immune cell survival and activation, including PI3K/AKT, NF-κB, and STAT3 signaling in B cells. At the same time, phosphorylation of the transcription factor CREB increased.
These findings suggest that nerandomilast modulates immune signaling networks that regulate B cell activation and pathogenic antibody production. Investigators concluded that the phosphodiesterase 4B inhibitor may represent a promising therapeutic candidate for idiopathic inflammatory myopathy–associated interstitial lung disease and warrants further investigation.
Reference
Liu Y et al. Nerandomilast attenuates idiopathic inflammatory myopathy-associated interstitial lung disease via inhibiting proliferation and differentiation of B cells. Front Immunol. 2026;DOI:10.3389/fimmu.2026.1771007.
