PMID- 26283632 OWN - NLM STAT- MEDLINE DCOM- 20160520 LR - 20220309 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 17 IP - 1 DP - 2015 Aug 18 TI - Nilotinib (Tasigna) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial. PG - 213 LID - 10.1186/s13075-015-0721-3 [doi] LID - 213 AB - INTRODUCTION: 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 (Tasigna). METHODS: Ten 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. RESULTS: Patients 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. CONCLUSION: Nilotinib 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 REGISTRATION: Clinicaltrials.gov NCT01166139 , July 1, 2010. FAU - Gordon, Jessica K AU - Gordon JK AD - Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. gordonj@hss.edu. FAU - Martyanov, Viktor AU - Martyanov V AD - Geisel School of Medicine at Dartmouth, Department of Genetics, Remsen 7400, Hanover, NH, 03755, USA. Viktor.Martyanov@dartmouth.edu. FAU - Magro, Cynthia AU - Magro C AD - Weill Cornell Medical Center, Department of Dermatopathology, 525 East 68th St, New York, NY, 10065, USA. cym2003@med.cornell.edu. FAU - Wildman, Horatio F AU - Wildman HF AD - Weill Cornell Medical Center, Department of Dermatology, 1305 York Ave, New York, NY, 10021, USA. hfw2001@med.cornell.edu. FAU - Wood, Tammara A AU - Wood TA AD - Geisel School of Medicine at Dartmouth, Department of Genetics, Remsen 7400, Hanover, NH, 03755, USA. Tammara.A.Wood@dartmouth.edu. FAU - Huang, Wei-Ti AU - Huang WT AD - Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. yorick838@gmail.com. FAU - Crow, Mary K AU - Crow MK AD - Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. crowm@hss.edu. FAU - Whitfield, Michael L AU - Whitfield ML AD - Geisel School of Medicine at Dartmouth, Department of Genetics, Remsen 7400, Hanover, NH, 03755, USA. Michael.L.Whitfield@dartmouth.edu. FAU - Spiera, Robert F AU - Spiera RF AD - Department of Rheumatology, Hospital for Special Surgery, 535 East 70th St, New York, NY, 10021, USA. spierar@hss.edu. LA - eng SI - GEO/GSE65405 SI - ClinicalTrials.gov/NCT01166139 GR - P30 AR061271/AR/NIAMS NIH HHS/United States GR - P30 CA023108/CA/NCI NIH HHS/United States GR - U19 AI056363/AI/NIAID NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150818 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (Receptors, Transforming Growth Factor beta) RN - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta) RN - F41401512X (nilotinib) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Anemia/chemically induced MH - Cardiovascular Diseases/chemically induced MH - Female MH - Headache/chemically induced MH - Humans MH - Male MH - Middle Aged MH - Nausea/chemically induced MH - Oligonucleotide Array Sequence Analysis MH - Pilot Projects MH - Protein Kinase Inhibitors/adverse effects/therapeutic use MH - Pyrimidines/adverse effects/*therapeutic use MH - Receptor, Platelet-Derived Growth Factor beta/genetics MH - Receptors, Transforming Growth Factor beta/genetics MH - Scleroderma, Diffuse/*drug therapy/genetics/pathology MH - Signal Transduction/genetics MH - Skin/*drug effects/metabolism/pathology MH - Transcriptome/*drug effects/genetics MH - Treatment Outcome MH - Young Adult PMC - PMC4538758 EDAT- 2015/08/19 06:00 MHDA- 2016/05/21 06:00 PMCR- 2015/08/18 CRDT- 2015/08/19 06:00 PHST- 2015/01/13 00:00 [received] PHST- 2015/07/20 00:00 [accepted] PHST- 2015/08/19 06:00 [entrez] PHST- 2015/08/19 06:00 [pubmed] PHST- 2016/05/21 06:00 [medline] PHST- 2015/08/18 00:00 [pmc-release] AID - 10.1186/s13075-015-0721-3 [pii] AID - 721 [pii] AID - 10.1186/s13075-015-0721-3 [doi] PST - epublish SO - Arthritis Res Ther. 2015 Aug 18;17(1):213. doi: 10.1186/s13075-015-0721-3.