title: Elevation of serum immunoglobulin free light chains during the preclinical period of rheumatoid arthritis.
abstract: OBJECTIVE
  Immunoglobulin free light chains (FLC) represent biomarkers of B cell activity in rheumatoid arthritis (RA) and are associated with all-cause mortality in the general population. Our objective was to evaluate the relationships of serum FLC to preclinical disease, RA characteristics, and mortality in RA compared to non-RA subjects.
  
  
  METHODS
  A population-based study in Olmsted County, Minnesota, USA, was performed by crosslinking a large cohort in the general population having available serum FLC measurements with established RA incidence and prevalence cohorts. Serum κ, λ, and total FLC and their trends relative to RA incidence were compared between RA and non-RA subjects. Regression models were used to determine the associations between FLC, disease characteristics, and mortality, testing for differential effects of FLC on mortality in RA.
  
  
  RESULTS
  Among 16,609 subjects, 270 fulfilled the criteria for RA at the time of FLC measurement. Mean total FLC were significantly higher in RA compared to non-RA subjects (4.2 vs 3.3 mg/dl, p < 0.001). FLC became elevated 3-5 years before the clinical onset of RA and remained elevated during followup. Polyclonal FLC were found to predict higher mortality in persons with RA, though elevation to the highest decile had a relatively lower effect on mortality in RA compared to non-RA subjects.
  
  
  CONCLUSIONS
  Elevation of serum FLC precedes the development of RA and may be useful in monitoring B cell activity and disease progression. FLC are associated with mortality among patients with RA as well as the general population.
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Deng
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Crowson
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Rajkumar
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Angela
authors.initials: A
authors.lastname: Dispenzieri
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Dirk R
authors.initials: DR
authors.lastname: Larson
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Terry M
authors.initials: TM
authors.lastname: Therneau
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Matteson
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kyle
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Katzmann
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic.
authors.forename: Sherine E
authors.initials: SE
authors.lastname: Gabriel
authors.affiliation: From the Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China; Department of Health Sciences Research, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.X. Deng, MD, Department of Rheumatology and Immunology, Peking University Third Hospital, and formerly Research Trainee, Division of Rheumatology, Departments of Medicine and Immunology, Mayo Clinic; C.S. Crowson, MS, Associate Professor of Medicine, Assistant Professor of Biostatistics; T.M. Therneau, PhD, Professor of Biostatistics, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; S.V. Rajkumar, MD, Professor of Medicine, Division of Hematology, Department of Medicine; A. Dispenzieri, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology; R.A. Kyle, MD, Professor of Medicine, Professor of Laboratory Medicine and Pathology, Division of Hematology, Department of Medicine; E.L. Matteson, MD, MPH, Professor of Medicine; S.E. Gabriel, MD, MSc, Professor of Epidemiology, Professor of Medicine, Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Health Sciences Research; J.M. Davis III, MD, MS, Associate Professor of Medicine, Division of Rheumatology, Department of Medicine; J.A. Katzmann, PhD, Assistant Professor of Microbiology, Associate Professor of Laboratory Medicine and Pathology, Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic, and the Mayo Clinic College of Medicine; D.R. Larson, MS, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic. davis.john4@mayo.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Davis
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000453:epidemiology / Q000276:immunology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000097:blood*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D008910:Minnesota / Q000453:epidemiology; D015995:Prevalence; D062706:Prodromal Symptoms
chemical_list: D007147:Immunoglobulin Light Chains
keywords: AUTOIMMUNITY; B CELL; BIOMARKERS; MORTALITY