Between 1988 and 2012, the prevalence of antinuclear antibodies in the United States increased from 11% to 15.9%, especially among adolescents, males, and non-Hispanic whites.
The finding comes from a retrospective, cross-sectional analysis of serum samples from individuals who participated in the U.S. National Health and Nutrition Examination Survey over three time periods: 1988-1991, 1999-2004, and 2011-2012.
“Autoimmune diseases are a diverse group of disorders characterized by damaging immune responses to self-antigens and, for the most part, are of unknown etiology,” authors led by Gregg E. Dinse, ScD, wrote in a study published in Arthritis & Rheumatology. “They are thought to impact 3%-5% of the population, with rising rates noted several decades ago. Recent studies suggest continued increases for certain autoimmune diseases, but it is unclear whether these trends are due to changes in recognition and diagnosis, or are true temporal changes in incidence.”
Dr. Dinse, of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and his colleagues evaluated sera samples of 14,211 survey participants aged 12 years and older at 1:80 dilution for antinuclear antibodies (ANA) using a standard indirect immunofluorescence assay (HEp-2 assay). The samples that received a grade of 3 or 4 on a 0-4 scale (compared with standard references, with values of 1-4 indicating positivity) underwent additional assessment by sequential ANA titers up to 1:1,280 dilution. To estimate changes in ANA prevalence over the time periods, they used logistic regression adjusted for age, sex, race/ethnicity, and survey design variables.
The researchers observed an ANA prevalence of 11% in 1988-1991, 11.5% in 1999-2004, and 15.9% in 2011-2012. This corresponds to 22, 27, and 41 million affected individuals, respectively. Females were more likely than males to have ANA (odds ratios of 2.53, 2.97, and 1.94 in 1988-1991, 1999-2004, and 2011-2012, respectively; P less than .0001), as were older adults relative to adolescents (ORs of 3.63, 1.80, and 1.71; P less than .002). Among adolescents, the prevalence of ANA rose steeply, with odds ratios of 2.02 in 1999-2004 and 2.88 in 2011-2012 in the second and third time periods relative to the first (trend P less than .0001). The researchers also found that, compared with non-Hispanic whites, the odds of having ANA were higher for non-Hispanic blacks (OR, 1.75) and Mexican-Americans (OR, 1.87) in 1988-1991, but racial/ethnic differences diminished in 1999-2004 and 2011-2012.
After adjustment for covariates, the researchers found that the estimated odds ratios for the second and third time periods relative to the first were 1.02 and 1.47, respectively, reflecting an overall ANA time trend (P less than .0001). Increases in ANA prevalence among cohorts did not correlate with contemporaneous trends in body mass index, smoking, or alcohol consumption.
Dr. Dinse and his colleagues acknowledged certain limitations of the study, including the fact that associations were based on cross-sectional data rather than repeated measures, and that some variables were self-reported, including the limited questionnaire data on autoimmune diseases.
Dr. David S. Pisetsky
In an interview, David S. Pisetsky, MD, professor of medicine/rheumatology and immunology at Duke University, Durham, N.C., characterized the study findings as “hypothesis generating” and said that he would like to know if the researchers would find the same results if they used a different ANA assay. “There’s a lot of variability from ANA kit to ANA kit – much greater than what was thought,” said Dr. Pisetsky, who is an authority on the topic. “One thing that needs to be done is to find out what the frequency is with other tests. One should recognize that the actual frequency is going to vary by the assay used. In another test format, the frequency may have been lower; it could have been higher.”
He added that the precise reasons why the prevalence of ANAs are rising in the general population remains elusive. “We know the target antigens in people with autoantibody-associated rheumatic disease,” Dr. Pisetsky said. “But what we don’t know a lot of times is, what are the target antigens in the otherwise healthy population? There has only been one antibody system that people have felt is associated with the otherwise healthy population. Those are called anti-DFS-70 antibodies, but there is even uncertainty about those. If you know what the antigens recognized were, then I think you could begin to speculate more about what’s going on in the population that’s increasing the frequency [of ANAs].”
In an accompanying editorial, Richard J. Bucala, MD, chief of rheumatology, allergy, and immunology at Yale University, New Haven, Conn., noted that the origins of autoantibodies in different rheumatic diseases and the steps that lead to disease progression remain elusive. “Modern societies experience an ever increasing variety of exposures due to travel and population migration, an increase in both the internationalization of agriculture and the industrialization of food production, a higher environmental burden of synthetic chemicals, emerging pathogens, and the inexorable effects of climate change,” Dr. Bucala wrote. “The speed and intensity of these influences is arguably unprecedented in human history and clearly outpace the possibility of protective genetic mechanisms to evolve and adapt.” He went on to note that the study’s findings “give impetus to multidisciplinary efforts aimed at preventative strategies, identifying environmental hazards, defining high-risk individuals, and preventing disease development in susceptible populations.”
The study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. The authors reported having no disclosures.
SOURCE: Dinse G et al. Arthritis Rheumatol. 2020 April 7. doi: 10.1002/ART.41214.