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

Abstract

BackgroundThere 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).MethodsPrimary 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.ResultsDasatinib 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).ConclusionsIn 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 registrationClinicaltrials.gov NCT00764309

Senescence Signature in Skin Biopsies From Systemic Sclerosis Patients Treated With Senolytic Therapy: Potential Predictor of Clinical Response?

“…Similarly to IPF, systemic sclerosis (SSc) is commonly complicated by fibrotic interstitial lung disease (ILD) and presently lacks approved therapies. To address the potential pathogenic role of cellular senescence in SSc‐associated ILD (SSc‐ILD), we reexamined our results from a recent single‐arm clinical trial of dasatinib , in which 12 patients with SSc‐ILD received treatment for 169 days. We sought to investigate changes in skin SASP gene signature across clinical improvers (defined as a decrease of >5 points or >20% from baseline in the modified Rodnan skin thickness score , a validated measure of SSc skin involvement) and in non‐improvers.…”

Prospects for Stratified and Precision Medicine in Systemic Sclerosis Treatment

“…Gene expression data from skin biopsies of patients treated with dasatinib for ILD were analysed. Of those that improved (defined as change in mRSS 9 5 points or decrease 9 20% from baseline), their gene expression subset was consistent with fibroproliferative or normal-like subsets, whereas the majority of non-improvers were in the inflammatory subset [53]. The pathways that were downregulated post-treatment in improvers included fibrotic gene subsets (e.g., PI3K/AKT/MTOR signalling and TGF-β signalling), as well as inflammatory pathways including IFNα/IFNγ response and TNFα/NF B signalling, whereas in the non-improvers, the gene expression in these pathways did not change.…”

Immunotherapy of systemic sclerosis

“…106 In a safety and pharmacokinetics study of 9 months duration, dasatinib improved skin score and stabilized lung function in few SSc patients. 107 The jury is still out for this class of drugs in SSc because of moderate therapeutic efficacy and serious toxicity. 26…”