title: Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis.
abstract: BACKGROUND
  Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.
  
  
  METHODS
  Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.
  
  
  RESULTS
  Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ≥30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.
  
  
  CONCLUSIONS
  Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00442611. Registered 1 March 2007.
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. Eliza-Chakravarty@omrf.org.
authors.forename: Eliza F
authors.initials: EF
authors.lastname: Chakravarty
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Viktor.Martyanov@dartmouth.edu.
authors.forename: Viktor
authors.initials: V
authors.lastname: Martyanov
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. fiorentino@stanford.edu.
authors.forename: David
authors.initials: D
authors.lastname: Fiorentino
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Tammara.A.Wood@dartmouth.edu.
authors.forename: Tammara A
authors.initials: TA
authors.lastname: Wood
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. djhaddon@stanford.edu.
authors.forename: David James
authors.initials: DJ
authors.lastname: Haddon
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. justin.ansel.jarrell@gmail.com.
authors.forename: Justin Ansel
authors.initials: JA
authors.lastname: Jarrell
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. pjutz@stanford.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. genovese@stanford.edu.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Michael.L.Whitfield@dartmouth.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. shauwei@stanford.edu.|Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. shauwei@stanford.edu.|Palo Alto VA Health Care System, Palo Alto, CA, USA. shauwei@stanford.edu.
authors.forename: Lorinda
authors.initials: L
authors.lastname: Chung
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use*; D000328:Adult; D018106:CD28 Antigens / Q000096:biosynthesis* / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D045743:Scleroderma, Diffuse / Q000188:drug therapy*
chemical_list: D018106:CD28 Antigens; D007166:Immunosuppressive Agents; C585279:TMIGD2 protein, human; D000069594:Abatacept