Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease.

Autor: Martyanov V; Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America., Kim GJ; David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States of America., Hayes W; Bristol-Myers Squibb, Princeton, NJ, United States of America., Du S; Bristol-Myers Squibb, Princeton, NJ, United States of America., Ganguly BJ; Bristol-Myers Squibb, Princeton, NJ, United States of America., Sy O; Bristol-Myers Squibb, Princeton, NJ, United States of America., Lee SK; Bristol-Myers Squibb, Princeton, NJ, United States of America., Bogatkevich GS; Medical University of South Carolina, Charleston, SC, United States of America., Schieven GL; Bristol-Myers Squibb, Princeton, NJ, United States of America., Schiopu E; University of Michigan Health System, Ann Arbor, MI, United States of America., Marangoni RG; Northwestern Scleroderma Program, Feinberg School of Medicine, Chicago, IL, United States of America., Goldin J; David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States of America., Whitfield ML; Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America., Varga J; Northwestern Scleroderma Program, Feinberg School of Medicine, Chicago, IL, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2017 Nov 09; Vol. 12 (11), pp. e0187580. Date of Electronic Publication: 2017 Nov 09 (Print Publication: 2017).
DOI: 10.1371/journal.pone.0187580
Abstrakt: Background: There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).
Methods: Primary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169.
Results: Dasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313).
Conclusions: In patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes.
Trial Registration: Clinicaltrials.gov NCT00764309.
Databáze: MEDLINE
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