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Tolerability and Safety of Nintedanib and Immunosuppression in Autoimmune Inflammatory Myopathy and Progressive Pulmonary Fibrosis

ABSTRACT: Introduction: Autoimmune-inflammatory myopathy related interstitial lung disease (AIM-ILD) are often progressive and fibrotic. Given the rarity of this disease, little is known about the safety and tolerability of nintedanib, an anti-fibrotic treatment, in combination with immunosuppression in this population. The objective of this single-arm, open-label trial was to assess safety and tolerability of nintedanib in AIM-ILD, and to determine if peripheral blood cell gene expression changes with administration of nintedanib. Methods: Patients with progressive, fibrotic AIM-ILD on background immunosuppression enrolled in this trial were given nintedanib for 24 weeks. Primary endpoint was the percentage of subjects who took 90% or more of the study drug doses. Secondary endpoints included safety (adverse events) and efficacy (lung function) outcomes. Bulk RNA sequencing of peripheral blood was performed at baseline and each subsequent visits to examine gene expression. Results: Eleven participants were enrolled, of which nine completed the study visits as per protocol at 24 weeks. The trial was discontinued due to slow recruitment. Only 3 (27%) participants took 90% or more doses of nintedanib. Drug compliance ranged from 27% to 95%. The most common adverse events were diarrhea, nausea / vomiting, and abdominal pain. There were no significant changes in lung function over time. No difference in gene expression over time was identified. Conclusions: Our trial was limited by small sample size and challenging recruitment, making clear conclusions on safety and tolerability difficult. The nintedanib treatment did not induce measurable gene expression changes in peripheral blood. Based on this small population, tolerability of nintedanib with immunosuppression in AIM-ILD appears challenging.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299128 | GEO | 2026/08/05

REPOSITORIES: GEO

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Project description:Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes. References: Hallal, Mahmoud, Sophie Braga-Lagache, Jovana Jankovic, Cedric Simillion, Rémy Bruggmann, Anne-Christine Uldry, Ramanjaneyulu Allam, Manfred Heller, and Nicolas Bonadies. 2021. “Inference of Kinase-Signaling Networks in Human Myeloid Cell Line Models by Phosphoproteomics Using Kinase Activity Enrichment Analysis (KAEA).” BMC Cancer 21 (1): 789.

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Tolerability and Safety of Nintedanib and Immunosuppression in Autoimmune Inflammatory Myopathy and Progressive Pulmonary Fibrosis

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