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

Abstract

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 autoantibodynegative (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 organspecific (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.

Latent rheumatic, thyroid and phospholipid autoimmunity in hospitalized patients with COVID-19

“…Autoimmunity is a continuum spectrum phenomenon ranging from latent autoimmunity (i.e., pre-clinical disease) to over AD ( Figure 3 ) [ 21 , [23] , [24] , [25] , [26] ]. Little is known about the precise frequency of autoantibodies in patients with COVID-19, and their role with clinical outcomes.…”

Population-based estimates of humoral autoimmunity from the U.S. National Health and Nutrition Examination Surveys, 1960–2014

“…Although a fraction of mild cases might never progress, clinical and public health surveillance of the full spectrum of AID disease is essential, because a significant fraction of patients progress from preclinical illness (positive autoantibodies or biomarkers only) to subclinical illness (few or no clinical symptoms but positive autoantibody, laboratory, and/or imaging studies) to overt, classically active disease [28,29]. Individuals with preclinical, autoantibody-positive disease have been shown recently to be at high risk of developing AID such as family members of AID cases, [30], and clinical prevention trials in rheumatoid arthritis and autoimmune diabetes are currently addressing this concern [31][32][33][34][35]. Most cases of subclinical AID and many cases of mild AID are not currently detected; in the general population, the number of persons at risk of AID and those with undiagnosed AID may be large.…”

Challenges and Opportunities: Using Omics to Generate Testable Insights Into Pathogenic Mechanisms in Preclinical Seropositive Rheumatoid Arthritis

“…With these now widely replicated findings, ongoing questions relevant to our contemporary understanding of the natural history of RA currently include those addressing what immune processes drive the initial break in tolerance to citrullinated and other self antigens during this asymptomatic preclinical period, and how the disease process then transitions to involve the joints, with the potential for eventual destruction. These are also questions of increasing relevance across the field of autoimmune disease research, as many other such diseases, including type 1 diabetes and systemic lupus erythematosus, clearly evolve through the same type of autoantibody‐positive preclinical period and exhibit similar forms of immune dysregulation during that time (5), including involvement of autoantibodies that can also cross these disease boundaries throughout the disease course (6). In this issue of Arthritis & Rheumatology , O’Neil and colleagues (7) add important information to our understanding of these concepts in the preclinical RA period.…”