title: Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity.
abstract: Systemic sclerosis (SSc) is a rare autoimmune disease with the highest case-fatality rate of all connective tissue diseases. Current efforts to determine patient response to a given treatment using the modified Rodnan skin score (mRSS) are complicated by interclinician variability, confounding, and the time required between sequential mRSS measurements to observe meaningful change. There is an unmet critical need for an objective metric of SSc disease severity. Here, we performed an integrated, multicohort analysis of SSc transcriptome data across 7 datasets from 6 centers composed of 515 samples. Using 158 skin samples from SSc patients and healthy controls recruited at 2 centers as a discovery cohort, we identified a 415-gene expression signature specific for SSc, and validated its ability to distinguish SSc patients from healthy controls in an additional 357 skin samples from 5 independent cohorts. Next, we defined the SSc skin severity score (4S). In every SSc cohort of skin biopsy samples analyzed in our study, 4S correlated significantly with mRSS, allowing objective quantification of SSc disease severity. Using transcriptome data from the largest longitudinal trial of SSc patients to date, we showed that 4S allowed us to objectively monitor individual SSc patients over time, as (a) the change in 4S of a patient is significantly correlated with change in the mRSS, and (b) the change in 4S at 12 months of treatment could predict the change in mRSS at 24 months. Our results suggest that 4S could be used to distinguish treatment responders from nonresponders prior to mRSS change. Our results demonstrate the potential clinical utility of a novel robust molecular signature and a computational approach to SSc disease severity quantification.
authors.affiliation: Institute for Immunity, Transplantation, and Infection.|Division of Biomedical Informatics Research, Department of Medicine, Stanford University, California, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Lofgren
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Monique
authors.initials: M
authors.lastname: Hinchcliff
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Carns
authors.affiliation: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Tammara
authors.initials: T
authors.lastname: Wood
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aren
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Arroyo
authors.affiliation: Division of Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Peggie
authors.initials: P
authors.lastname: Cheung
authors.affiliation: Division of Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Kuo
authors.affiliation: Division of Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Valenzuela
authors.affiliation: Department of Dermatology.
authors.forename: Anna
authors.initials: A
authors.lastname: Haemel
authors.affiliation: Pulmonary Division, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.affiliation: Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gordon
authors.affiliation: Department of Rheumatology, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Spiera
authors.affiliation: Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center Houston, Houston, Texas, USA.
authors.forename: Shervin
authors.initials: S
authors.lastname: Assassi
authors.affiliation: Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Boin
authors.affiliation: Division of Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.|Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.|Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Lorinda
authors.initials: L
authors.lastname: Chung
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fiorentino
authors.affiliation: Institute for Immunity, Transplantation, and Infection.|Division of Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.affiliation: Institute for Immunity, Transplantation, and Infection.|Division of Biomedical Informatics Research, Department of Medicine, Stanford University, California, USA.
authors.forename: Purvesh
authors.initials: P
authors.lastname: Khatri