title: Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis.
abstract: Heterogeneity in systemic sclerosis (SSc) confounds clinical trials. We previously identified "intrinsic" gene expression subsets by analysis of SSc skin. Here we test the hypotheses that skin gene expression signatures including intrinsic subset are associated with modified Rodnan skin score (MRSS) improvement during mycophenolate mofetil (MMF) treatment. Gene expression and intrinsic subset assignment were measured in 12 SSc patients' biopsies and 10 controls at baseline, and from serial biopsies of 1 cyclophosphamide-treated patient and 9 MMF-treated patients. Gene expression changes during treatment were determined using paired t-tests corrected for multiple hypothesis testing. MRSS improved in four of seven MMF-treated patients classified as the inflammatory intrinsic subset. Three patients without MRSS improvement were classified as normal-like or fibroproliferative intrinsic subsets. A total of 321 genes (false discovery rate (FDR)<5%) were differentially expressed at baseline between patients with and without MRSS improvement during treatment. The expression of 571 genes (FDR<10%) changed between pre- and post-MMF treatment biopsies for patients showing MRSS improvement. Gene expression changes in skin are only seen in patients with MRSS improvement. Baseline gene expression in skin, including intrinsic subset assignment, may identify SSc patients whose MRSS will improve during MMF treatment, suggesting that gene expression in skin may allow targeted treatment in SSc.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. m-hinchcliff@northwestern.edu
authors.forename: Monique
authors.initials: M
authors.lastname: Hinchcliff
authors.forename: Chiang-Ching
authors.initials: CC
authors.lastname: Huang
authors.forename: Tammara A
authors.initials: TA
authors.lastname: Wood
authors.forename: J
authors.initials: J
authors.lastname: Matthew Mahoney
authors.forename: Viktor
authors.initials: V
authors.lastname: Martyanov
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Zenshiro
authors.initials: Z
authors.lastname: Tamaki
authors.forename: Jungwha
authors.initials: J
authors.lastname: Lee
authors.forename: Mary
authors.initials: M
authors.lastname: Carns
authors.forename: Sofia
authors.initials: S
authors.lastname: Podlusky
authors.forename: Arlene
authors.initials: A
authors.lastname: Sirajuddin
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.forename: Rowland W
authors.initials: RW
authors.lastname: Chang
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D016000:Cluster Analysis; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D018740:Genetic Heterogeneity / Q000187:drug effects; D005819:Genetic Markers / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011237:Predictive Value of Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D012879:Skin Physiological Phenomena / Q000187:drug effects* / Q000235:genetics*; D059467:Transcriptome / Q000187:drug effects; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid