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Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients


James JA1, Chen H2, Young KA3, Bemis EA3, Seifert J3, Bourn RL2, Deane KD3, Demoruelle MK3, Feser M3, O'Dell JR4, Weisman MH5, Keating RM6, Gaffney PM2, Kelly JA2, Langefeld CD7, Harley JB8, Robinson W9, Hafler DA10, O'Connor KC10, Buckner J11, Guthridge JM2, Norris JM3, Holers VM3. EBioMedicine. 2019 Apr;42:76-85. doi: 10.1016/j.ebiom.2019.03.063. Epub 2019 Apr 3.

Author Information

1 Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: judith-james@omrf.org.

2 Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

3 University of Colorado, Aurora, CO, USA.

4 University of Nebraska Medical Center, Omaha, NE, USA.

5 Cedars-Sinai Medical Center, Los Angeles, California, USA.

6 The University of Chicago, Chicago, IL, USA.

7 Wake Forest School of Medicine, Winston-Salem, NC, USA.

8 Cincinnati Children's Hospital Medical Center, The University of Cincinnati College of Medicine, and Cincinnati US Department of Veterans Affairs VA Medical Center, Cincinnati, OH, USA.

9 Stanford University, Palo Alto, CA, USA.

10 Yale School of Medicine, New Haven, CT, USA.

11 Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.



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.


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.


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.


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.