Abstract
IntroductionTyrosine kinase inhibitors (TKI) are medications of interest in the treatment of Systemic Sclerosis (SSc) because of their ability to inhibit pathways involved in fibrosis. In this open-label pilot trial, our objectives were to assess the safety, efficacy, and molecular change associated with treatment of patients with diffuse cutaneous (dc)SSc with the TKI nilotinib (Tasigna™).MethodsTen adult patients with early dcSSc were treated with nilotinib. Primary endpoints were safety and change in modified Rodnan Skin Score (MRSS) after 6 months. Lesional skin biopsies at baseline, 6 and 12 months of treatment were assessed by histopathology, immunohistochemistry, and DNA microarray.ResultsPatients had early and active dcSSc with median disease duration of 0.7 years (range 0.5, 1.7) and increasing MRSS in the month prior to baseline (mean +2.9, p=0.02). Seven out of ten patients completed 6 and 12 months of treatment. Seventy-one adverse events (AEs) including 2 serious AEs were observed, and 92 % of AEs were grade 1-2. Two patients discontinued the medication due to mild QTc prolongation. MRSS improved by a mean of 4.2 points (16 %) at 6 months and by 6.3 points (23 %) at 12 months in the 7 completers, p=0.02 and 0.01, respectively. Patients with a decrease in MRSS >20 % from baseline at 12 months (classified as improvers) had significantly higher expression of transforming growth factor beta receptor (TGFBR) and platelet-derived growth factor receptor beta (PDGFRB) signaling genes at baseline than non-improvers, and the expression of these genes significantly decreased in improvers post-treatment.ConclusionNilotinib was well tolerated by the majority of patients in this study, with tolerability limited primarily by mild QTc-prolongation. Significant MRSS improvement was observed in these early, active patients, but is not conclusive of treatment effect given the open-label study-design and small number of patients in this pilot study. Improvers had higher levels of expression of genes associated with TGFBR and PDGFRB signaling at baseline, and a significant decrease in the expression of these genes occurred only in patients with higher MRSS improvement. The findings of this pilot study warrant more conclusive evaluation.Trial registrationClinicaltrials.gov NCT01166139, July 1, 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0721-3) contains supplementary material, which is available to authorized users.
Highlights
Tyrosine kinase inhibitors (TKI) are medications of interest in the treatment of Systemic Sclerosis (SSc) because of their ability to inhibit pathways involved in fibrosis
We identified 19 genes involved in transforming growth factor beta receptor (TGFBR) signaling and 50 genes involved in platelet-derived growth factor receptor beta (PDGFRB) signaling that comprised the core enrichment groups for these pathways in improvers based on gene set enrichment analysis (GSEA) results (Additional file 8)
We examined the expression of TGFBR and PDGFRB signaling gene sets across six completers, four improvers and two non-improvers at baseline and post treatment (Fig. 5)
Summary
Tyrosine kinase inhibitors (TKI) are medications of interest in the treatment of Systemic Sclerosis (SSc) because of their ability to inhibit pathways involved in fibrosis. In this open-label pilot trial, our objectives were to assess the safety, efficacy, and molecular change associated with treatment of patients with diffuse cutaneous (dc)SSc with the TKI nilotinib (TasignaTM). Nilotinib (TasignaTM; Novartis, Basel, Switzerland) is a tyrosine kinase inhibitor (TKI) with antagonistic activity against Abelson tyrosine kinase (c-Abl), the PDGF receptor (PDGFR), and other tyrosine kinases It is approved in the USA for the treatment of chronic myelogenous leukemia (CML) [6]. These models have shortcomings in their ability to predict clinical impact in SSc [8]
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