title: Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment.
abstract: Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-β signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial.
  
  
  
  We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ≥ 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc.
  
  
  
  The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib.
  
  
  
  Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.gov NCT00555581 and NCT01166139.
authors.affiliation: From the Division of Immunology and Rheumatology, Stanford University School of Medicine; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford; Department of Rheumatology, Palo Alto VA Health Care System, Palo Alto, California; Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|D.J. Haddon, PhD, Research Associate, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine; H.E. Wand, BS, Genetic Counseling Candidate, Division of Immunology and Rheumatology, Stanford University School of Medicine; J.A. Jarrell, PhD Candidate, Immunology, Division of Immunology and Rheumatology, Stanford University School of Medicine; R.F. Spiera, MD, Professor of Clinical Medicine, Rheumatology and Director, Vasculitis and Scleroderma Program, Department of Rheumatology, Hospital for Special Surgery; P.J. Utz, MD, Professor of Medicine, Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine; J.K. Gordon, MD, Assistant Professor of Medicine, Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York; L.S. Chung, MD, MS, Associate Professor of Medicine, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine, and Department of Rheumatology, Palo Alto VA Health Care System.
authors.forename: D James
authors.initials: DJ
authors.lastname: Haddon
authors.affiliation: From the Division of Immunology and Rheumatology, Stanford University School of Medicine; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford; Department of Rheumatology, Palo Alto VA Health Care System, Palo Alto, California; Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|D.J. Haddon, PhD, Research Associate, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine; H.E. Wand, BS, Genetic Counseling Candidate, Division of Immunology and Rheumatology, Stanford University School of Medicine; J.A. Jarrell, PhD Candidate, Immunology, Division of Immunology and Rheumatology, Stanford University School of Medicine; R.F. Spiera, MD, Professor of Clinical Medicine, Rheumatology and Director, Vasculitis and Scleroderma Program, Department of Rheumatology, Hospital for Special Surgery; P.J. Utz, MD, Professor of Medicine, Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine; J.K. Gordon, MD, Assistant Professor of Medicine, Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York; L.S. Chung, MD, MS, Associate Professor of Medicine, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine, and Department of Rheumatology, Palo Alto VA Health Care System.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Wand
authors.affiliation: From the Division of Immunology and Rheumatology, Stanford University School of Medicine; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford; Department of Rheumatology, Palo Alto VA Health Care System, Palo Alto, California; Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|D.J. Haddon, PhD, Research Associate, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine; H.E. Wand, BS, Genetic Counseling Candidate, Division of Immunology and Rheumatology, Stanford University School of Medicine; J.A. Jarrell, PhD Candidate, Immunology, Division of Immunology and Rheumatology, Stanford University School of Medicine; R.F. Spiera, MD, Professor of Clinical Medicine, Rheumatology and Director, Vasculitis and Scleroderma Program, Department of Rheumatology, Hospital for Special Surgery; P.J. Utz, MD, Professor of Medicine, Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine; J.K. Gordon, MD, Assistant Professor of Medicine, Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York; L.S. Chung, MD, MS, Associate Professor of Medicine, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine, and Department of Rheumatology, Palo Alto VA Health Care System.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Jarrell
authors.affiliation: From the Division of Immunology and Rheumatology, Stanford University School of Medicine; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford; Department of Rheumatology, Palo Alto VA Health Care System, Palo Alto, California; Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|D.J. Haddon, PhD, Research Associate, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine; H.E. Wand, BS, Genetic Counseling Candidate, Division of Immunology and Rheumatology, Stanford University School of Medicine; J.A. Jarrell, PhD Candidate, Immunology, Division of Immunology and Rheumatology, Stanford University School of Medicine; R.F. Spiera, MD, Professor of Clinical Medicine, Rheumatology and Director, Vasculitis and Scleroderma Program, Department of Rheumatology, Hospital for Special Surgery; P.J. Utz, MD, Professor of Medicine, Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine; J.K. Gordon, MD, Assistant Professor of Medicine, Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York; L.S. Chung, MD, MS, Associate Professor of Medicine, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine, and Department of Rheumatology, Palo Alto VA Health Care System.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spiera
authors.affiliation: From the Division of Immunology and Rheumatology, Stanford University School of Medicine; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford; Department of Rheumatology, Palo Alto VA Health Care System, Palo Alto, California; Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|D.J. Haddon, PhD, Research Associate, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine; H.E. Wand, BS, Genetic Counseling Candidate, Division of Immunology and Rheumatology, Stanford University School of Medicine; J.A. Jarrell, PhD Candidate, Immunology, Division of Immunology and Rheumatology, Stanford University School of Medicine; R.F. Spiera, MD, Professor of Clinical Medicine, Rheumatology and Director, Vasculitis and Scleroderma Program, Department of Rheumatology, Hospital for Special Surgery; P.J. Utz, MD, Professor of Medicine, Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine; J.K. Gordon, MD, Assistant Professor of Medicine, Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York; L.S. Chung, MD, MS, Associate Professor of Medicine, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine, and Department of Rheumatology, Palo Alto VA Health Care System.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: From the Division of Immunology and Rheumatology, Stanford University School of Medicine; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford; Department of Rheumatology, Palo Alto VA Health Care System, Palo Alto, California; Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.|D.J. Haddon, PhD, Research Associate, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine; H.E. Wand, BS, Genetic Counseling Candidate, Division of Immunology and Rheumatology, Stanford University School of Medicine; J.A. Jarrell, PhD Candidate, Immunology, Division of Immunology and Rheumatology, Stanford University School of Medicine; R.F. Spiera, MD, Professor of Clinical Medicine, Rheumatology and Director, Vasculitis and Scleroderma Program, Department of Rheumatology, Hospital for Special Surgery; P.J. Utz, MD, Professor of Medicine, Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine; J.K. Gordon, MD, Assistant Professor of Medicine, Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York; L.S. Chung, MD, MS, Associate Professor of Medicine, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine, and Department of Rheumatology, Palo Alto VA Health Care System.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Gordon
authors.affiliation: From the Division of Immunology and Rheumatology, Stanford University School of Medicine; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford; Department of Rheumatology, Palo Alto VA Health Care System, Palo Alto, California; Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA. shauwei@stanford.edu.|D.J. Haddon, PhD, Research Associate, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine; H.E. Wand, BS, Genetic Counseling Candidate, Division of Immunology and Rheumatology, Stanford University School of Medicine; J.A. Jarrell, PhD Candidate, Immunology, Division of Immunology and Rheumatology, Stanford University School of Medicine; R.F. Spiera, MD, Professor of Clinical Medicine, Rheumatology and Director, Vasculitis and Scleroderma Program, Department of Rheumatology, Hospital for Special Surgery; P.J. Utz, MD, Professor of Medicine, Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine; J.K. Gordon, MD, Assistant Professor of Medicine, Rheumatology, Department of Rheumatology, Hospital for Special Surgery, New York; L.S. Chung, MD, MS, Associate Professor of Medicine, Immunology and Rheumatology, Division of Immunology and Rheumatology, Stanford University School of Medicine, and Department of Rheumatology, Palo Alto VA Health Care System. shauwei@stanford.edu.
authors.forename: Lorinda S
authors.initials: LS
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018925:Chemokines / Q000097:blood*; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D040901:Proteomics; D045743:Scleroderma, Diffuse / Q000097:blood* / Q000188:drug therapy; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018925:Chemokines; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate
keywords: AUTOANTIBODIES; DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS; IMATINIB; NILOTINIB; PROTEIN MICROARRAYS