TY - JOUR
T1 - Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients
AU - James, Judith A.
AU - Chen, Hua
AU - Young, Kendra A.
AU - Bemis, Elizabeth A.
AU - Seifert, Jennifer
AU - Bourn, Rebecka L.
AU - Deane, Kevin D.
AU - Demoruelle, M. Kristen
AU - Feser, Marie
AU - O'Dell, James R.
AU - Weisman, Michael H.
AU - Keating, Richard M.
AU - Gaffney, Patrick M.
AU - Kelly, Jennifer A.
AU - Langefeld, Carl D.
AU - Harley, John B.
AU - Robinson, William
AU - Hafler, David A.
AU - O'Connor, Kevin C.
AU - Buckner, Jane
AU - Guthridge, Joel M.
AU - Norris, Jill M.
AU - Holers, V. Michael
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/4
Y1 - 2019/4
N2 - Background: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs)of patients, who exhibit increased future risk for the same disease. Methods: Samples (n = 1321)from disease-specific autoantibody-positive (aAb+)systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D)patients; and unaffected aAb+ and autoantibody-negative (aAb–)SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS)were calculated. Findings: Alternative autoimmunity occurred in SLE patients (56%)and FDRs (57·4%), RA patients (32·6%)and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR]2·44)and expanded (OR 3·27)autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE)and organ-specific (T1D)autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.
AB - Background: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs)of patients, who exhibit increased future risk for the same disease. Methods: Samples (n = 1321)from disease-specific autoantibody-positive (aAb+)systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D)patients; and unaffected aAb+ and autoantibody-negative (aAb–)SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS)were calculated. Findings: Alternative autoimmunity occurred in SLE patients (56%)and FDRs (57·4%), RA patients (32·6%)and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR]2·44)and expanded (OR 3·27)autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE)and organ-specific (T1D)autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.
KW - Autoantibodies
KW - Genetic risk
KW - Lupus
KW - Relatives
KW - Rheumatoid arthritis
KW - Type I diabetes
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U2 - 10.1016/j.ebiom.2019.03.063
DO - 10.1016/j.ebiom.2019.03.063
M3 - Article
C2 - 30952617
AN - SCOPUS:85063743117
SN - 2352-3964
VL - 42
SP - 76
EP - 85
JO - EBioMedicine
JF - EBioMedicine
ER -