Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Does Treatment with Imatinib Modify Gene Expression in the Skin and Peripheral Blood Mononuclear Cells of Patient with Systemic Sclerosis?

Gordon1,  Jessica K., Spiera2,  Robert, Mersten1,  Jamie N., Wildman4,  Horatio F., Taimeh3,  Ziad, Hackett4,  Neil, Vukelic3,  Sasa

Hospital for Special Surgery, New York, NY
Hospital for Special Surgery, New York, NY
Hospital for Special Surgery
Weill-Cornell Medical College

Background:

Patients with Systemic Sclerosis (SSc) have been shown to have distinct patterns of gene expression in the skin and peripheral blood. In the skin these patterns correspond to clinical involvement. It is not known whether gene expression patterns in the skin correlate with those in the blood or if treatment leads to modulation of gene expression. We hypothesized that imatinib treatment would modulate gene expression in the skin and peripheral blood mononuclear cells (PBMC) of treated patients with diffuse cutaneous (dc)SSc.

Methods:

We performed gene expression profiling with microarray on RNA from skin biopsy and PBMC samples of 8 patients with dcSSc from the Imatinib clinical trial at our center. Patients selected had improvements of >= 5 points in their Modified Rodnan Skin Scores (MRSS) over 12 months. RNA was hybridized to Affymetrix Human U133 2.0 gene chips. Paired t-tests were performed using Genespring GX11 and Ingenuity Pathways was used to evaluate pathways of interest.

Results:

Patient characteristics: 63% female; median age: 44 [18, 71]; median disease duration: 1.8 years [0.3 to 8]; and median change in MRSS: -9 [-5 to -12]. In the skin treatment led to the differential expression of 433 genes at a p-value of 0.05 and a fold-change cut-off of 1.5 without multiple testing correction. In PBMC treatment led to differential expression of 534 genes at the same cut-off. In PBMC unsupervised hierarchical clustering demonstrated a primary separation of groups based on treatment status.

In both skin and blood we observed down-regulation of PI3K signaling with treatment. This included down-regulation of AKT2, PIK3R1, PIK3C2A, EEAl, and ITPRIPL2 in skin and down-regulation of AKT2, INPP4A, HIPK1, LIMK1, MAK, MAP2K6, and PTEN in blood. We were interested especially looking for changes in TGF-b and PDGFR signaling. In the skin there was down regulation of smad2 and AKT2, and in PBMC there was decreased expression the TGF-b Receptor 1, egr2 transcription factor, WNK1 and AKT2. In the skin there was increased expression of PDGFRL.

Other entities differentially regulated include in the skin down-regulation of NCOA3, ADAM10, ADAM17, vitamin D receptor, dihydrofolate reductase, Cxcl3, and integrin b1 as well as up-regulation for col1a1, col6a2, MAPK12, ADAMTS2, and the chemokines CCL 18, 26, 22, 13. In PBMC there was differential expression of the angiogenic mediators VEGFA (up) and flt1 (down.) There was also increased expression of thrombospondin1.

Conclusions:

Treatment with imatinib may lead to modulation of gene expression in skin and PBMC. Hierarchical clustering in PBMC is supportive of a treatment effect. One common pathway affected in skin and blood is PI3K signal transduction which was not expected but which may be pathogenically relevant in the transdifferentiation of myofibroblasts. It is important to note that the changes seen are modest and do not stand up to statistical correction for multiple testing in this small number of patients. We plan to analyze this data in the context of several controls – treated patients without clinical improvement, longitudinal disease controls, and healthy controls. Validation of this microarray data by qPCR is planned.

To cite this abstract, please use the following information:
Gordon, Jessica K., Spiera, Robert, Mersten, Jamie N., Wildman, Horatio F., Taimeh, Ziad, Hackett, Neil, et al; Does Treatment with Imatinib Modify Gene Expression in the Skin and Peripheral Blood Mononuclear Cells of Patient with Systemic Sclerosis? [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1990
DOI: 10.1002/art.29755

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