title: Discerning Risk of Disease Transition in Relatives of Systemic Lupus Erythematosus Patients Utilizing Soluble Mediators and Clinical Features.
abstract: Systemic lupus erythematosus (SLE) and other autoimmune diseases cause significant morbidity. Identifying populations at risk of developing SLE is essential for curtailing irreversible inflammatory damage. The aim of this study was to identify factors associated with transition to classified disease that would inform our understanding of the risk of SLE.
  
  
  
  Previously identified blood relatives of patients with SLE, who had <4 American College of Rheumatology (ACR) classification criteria for SLE at baseline, were enrolled in this follow-up study (n = 409 unaffected relatives). Participants provided detailed family, demographic, and clinical information, including the SLE-specific portion of the Connective Tissue Disease Screening Questionnaire (SLE-CSQ). Serum and plasma samples were tested for the presence of lupus-associated autoantibodies and 52 soluble mediators. Generalized estimating equations (GEEs) were applied to identify factors predictive of disease transition.
  
  
  
  Of the 409 unaffected relatives of SLE patients, 45 (11%) had transitioned to classified SLE at follow-up (mean time to follow-up 6.4 years). Relatives who transitioned to SLE displayed more lupus-associated autoantibody specificities and higher SLE-CSQ scores (P < 0.0001) at baseline than did relatives who did not transition. Importantly, those who had developed SLE during the follow-up period also had elevated baseline plasma levels of inflammatory mediators, including B lymphocyte stimulator, stem cell factor (SCF), and interferon-associated chemokines (P ≤ 0.02), with concurrent decreases in the levels of regulatory mediators, transforming growth factor β (TGFβ), and interleukin-10 (P ≤ 0.03). GEE analyses revealed that baseline SLE-CSQ scores or ACR scores (number of ACR criteria satisfied) and plasma levels of SCF and TGFβ, but not autoantibodies, were significant and independent predictors of SLE transition (P ≤ 0.03).
  
  
  
  Preclinical alterations in levels of soluble mediators may predict transition to classified disease in relatives of SLE patients. Thus, immune perturbations precede SLE classification and can help identify high-risk relatives for rheumatology referral and potential enrollment in prevention trials.
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Melissa E
authors.identifier: 0000-0002-6933-9745
authors.initials: ME
authors.lastname: Munroe
authors.affiliation: Colorado School of Public Health, Aurora.
authors.forename: Kendra A
authors.initials: KA
authors.lastname: Young
authors.affiliation: Medical University of South Carolina, Charleston.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Kamen
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Costenbader
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Weisman
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Mariko L
authors.initials: ML
authors.lastname: Ishimori
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wallace
authors.affiliation: Medical University of South Carolina, Charleston.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.affiliation: University of Texas Southwestern Medical Center, Dallas.
authors.forename: David R
authors.initials: DR
authors.lastname: Karp
authors.affiliation: Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Colorado School of Public Health, Aurora.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.affiliation: Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
mesh_terms: D001323:Autoantibodies / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment
chemical_list: D001323:Autoantibodies; D018836:Inflammation Mediators