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Antinuclear Antibodies and Autoimmune Disease

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The prevalence of autoimmune disease (AD), which collectively includes more than 80 conditions, has risen dramatically in the United States over the years, now impacting up to 10% of the population.1–3 Genetics, infections, and changes in environmental exposures may play a role in the increasing number of cases.3,4 To add to the complexity of the issue, gender and racial disparities exist among different autoimmune diseases. Overall, the conditions disproportionately afflict women,5 and research indicates that African Americans may be at a higher risk than European Americans for certain autoimmune conditions such as systemic lupus erythematosus (SLE) and scleroderma (systemic sclerosis).6–8 

Antinuclear antibodies (ANAs) are common biomarkers of autoimmune disorders, and recent research indicates that a rise in ANA presence in the US population has mirrored the increase of autoimmune disease in the past 25 years.9 The detection of ANAs may indicate the future development of an autoimmune disease and may even precede symptoms by years.9 Is ANA testing an effective proactive tool in the prevention of some autoimmune conditions?

A Rise in Antinuclear Antibodies

Antinuclear antibodies are a group of autoantibodies produced by the immune system that target and bind to contents of a cell’s nucleus. While minimal amounts of ANAs may be detected in some healthy people, larger amounts may indicate an autoimmune disorder. A 2020 cross-sectional study investigated the prevalence of ANAs in the US over a 25-year span, from 1988 to 2012.9 Investigators used blood test results (serum ANA measured by standard indirect immunofluorescence (IIF) assays on human epithelial type 2 (HEp-2) cells) from 14,211 participants aged 12 years or greater who participated in the National Health and Nutrition Examination Survey, with approximately one-third of the participants from each of three time periods: 1988-1991, 1999-2004, and 2011-2012.9 Results for each time period indicated the following ANA prevalence percentages and estimations of ANA-positive individuals:9

  • 1988-1991: 11.0% (~22 million)
  • 1999-2004: 11.5% (~27 million)
  • 2011-2012: 15.9% (~41 million)

The ANA prevalence increase was greatest from the second to the third time period. Researchers also noted that the increases were not due to other concurrent trends in obesity, smoking exposure, or alcohol consumption.9 Additional results from this study indicated that ANA prevalence specifically increased for:9

  • Both women and men, with men showing the greater increase.
  • Adults who were 50 years or older, with the noted potential influence of increased age-related exposures, such as medications.
  • Adolescents between 12 and 19 years of age, with positive ANA tests nearly doubling then tripling over the time periods (from 5% to 9% to 13%).
  • Non-Hispanic whites. Relative to race, results indicated higher ANA-positivity odds in non-Hispanic African Americans and Mexican Americans in 1988-1991, but racial differences decreased in the second and third time periods.

ANA Testing, Detection, and a Window of Opportunity

A positive ANA test means that autoantibodies have been detected within the system; however, this positive test may be present without any evidence of disease.10 Therefore, classification criteria for some autoimmune conditions such as SLE include both a detection of ANAs found through testing in addition to relevant clinical presentations.11,12 Different techniques are available for antibody screening such as immunofluorescence (IIF) assays and solid phase immunoassays, each with advantages and limitations.13 A standard screening for ANA detection is the IIF assay on HEp-2 cells,9,14 and in fluorescent ANA testing:10,15,16

  • Patient blood samples are often screened for ANA after being diluted 1:40 and 1:160 in a buffered solution with results reported in titers.
  • The higher the titer, the more autoantibodies are present in the sample.
  • Laboratories performing immunofluorescent ANA tests may report results for both the 1:40 and 1:160 dilutions.
  • At a dilution of 1:160, only 5% of healthy individuals may have a positive test for ANA.

While ANAs may be present in the body without any other indication of disease, for many patients, ANA levels may rise years before any autoimmune symptoms, or a clinical diagnosis.10,14

 

Studies have indicated autoantibodies as a predictor of conditions such as SLE, inflammatory bowel disease, type 1 diabetes, autoimmune skin disorders such as scleroderma, dermatitis herpetiformis, and psoriasis, and rheumatoid arthritis (RA).14,17–21 A 2015 cohort study investigated the positive predictive value (PPV) of autoantibodies for the development of RA in healthy relatives of patients with RA.19 Results indicated a 64% PPV of RA diagnosis at five years when serum levels of IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies were found at baseline.19

Can such a predictive window offer an opportunity for successful interventions to stop an autoimmune disease process before it emerges? Recent studies have suggested a need for more personalized data collection, such as genetics and combinations of biomarkers, and enhanced data analysis methods in research studies to increase the overall predictive power of ANAs and other autoantibodies.21,22 In a clinical setting, ANA testing may present a proactive opportunity to expand interventions that emphasize prevention of potential autoimmune disease through strategies that address factors common in the progression of autoimmune conditions such as chronic inflammation and impaired intestinal permeability.23 These proactive opportunities may ultimately improve health outcomes and promote wellness among a wide range of patients.

Learn more about autoantibodies, autoimmune conditions, clinical applications, and the latest research from functional medicine experts at IFM’s Immune Advanced Practice Module (APM).

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References

  1. National Institute of Allergy and Infectious Diseases. Autoimmune diseases. https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases. Published May 2, 2017. Accessed November 24, 2021.
  2. Hood E. Measuring autoimmunity in America. Environmental Factor. https://factor.niehs.nih.gov/2018/4/science-highlights/autoimmunity/index.htm. Published April 1, 2018. Accessed November 24, 2021.
  3. National Institute of Environmental Health Sciences. Autoimmune diseases. https://www.niehs.nih.gov/health/topics/conditions/autoimmune/index.cfm. Published July 12, 2021. Accessed November 24, 2021.
  4. National Institutes of Health. Marker of autoimmunity increases in the U.S. https://www.nih.gov/news-events/nih-research-matters/marker-autoimmunity-increases-us. Published April 21, 2020. Accessed November 24, 2021.
  5. Roberts MH, Erdei E. Comparative United States autoimmune disease rates for 2010–2016 by sex, geographic region, and race. Autoimmun Rev. 2020;19(1):102423. doi:10.1016/j.autrev.2019.102423.
  6. The Autoimmune Diseases Coordinating Committee. Progress in autoimmune diseases research: report to Congress. National Institutes of Health. https://www.niaid.nih.gov/sites/default/files/adccfinal.pdf. Published March 1, 2005. Accessed November 24, 2021.
  7. Somers EC, Marder W, Cagnoli P, et al. Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan Lupus Epidemiology and Surveillance program. Arthritis Rheumatol. 2014;66(2):369-378. doi:10.1002/art.38238.
  8. Ramos PS, Shedlock AM, Langefeld CD. Genetics of autoimmune diseases: insights from population genetics. J Hum Genet. 2015;60(11):657-664. doi:10.1038/jhg.2015.94.
  9. Dinse GE, Parks CG, Weinberg CR, et al. Increasing prevalence of antinuclear antibodies in the United States. Arthritis Rheumatol. 2020;72(6):1026-1035. doi:10.1002/art.41214.
  10.  American College of Rheumatology. Antinuclear antibodies (ANA). https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Antinuclear-Antibodies-ANA. Published March 2019. Accessed November 24, 2021.
  11.  Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78(9):1151-1159. doi:10.1136/annrheumdis-2018-214819.
  12.  Rösken GHJ, van Beek AA, Bakker-Jonges LE, Schreurs MWJ. Antinuclear antibodies in systemic autoimmune disease. Ned Tijdschr Geneeskd. 2020;164:D4066.
  13.  Bossuyt X, De Langhe E, Borghi MO, Meroni PL. Understanding and interpreting antinuclear antibody tests in systemic rheumatic diseases. Nat Rev Rheumatol. 2020;16(12):715-726. doi:10.1038/s41584-020-00522-w.
  14.  Pérez D, Gilburd B, Cabrera-Marante Ó, et al. Predictive autoimmunity using autoantibodies: screening for anti-nuclear antibodies. Clin Chem Lab Med. 2018;56(10):1771-1777. doi:10.1515/cclm-2017-0241.
  15.  Bloch DB. Patient education: antinuclear antibodies (ANA) (beyond the basics). UpToDate. https://www.uptodate.com/contents/antinuclear-antibodies-ana-beyond-the-basics. Published June 23, 2021. Accessed November 24, 2021.
  16.  Tan E, Feltkamp T, Smolen J, et al. Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum. 1997;40(9):1601-1611. doi:10.1002/art.1780400909.
  17.  Lyons R, Narain S, Nichols C, Satoh M, Reeves WH. Effective use of autoantibody tests in the diagnosis of systemic autoimmune disease. Ann N Y Acad Sci. 2006;1050(1):217-228. doi:10.1196/annals.1313.023.
  18.  Nancy A-L, Yehuda S. Prediction and prevention of autoimmune skin disorders. Arch Dermatol Res. 2009;301(1):57-64. doi:10.1007/s00403-008-0889-3.
  19.  Ramos-Remus C, Castillo-Ortiz JD, Aguilar-Lozano L, et al. Autoantibodies in prediction of the development of rheumatoid arthritis among healthy relatives of patients with the disease. Arthritis Rheumatol. 2015;67(11):2837-2844. doi:10.1002/art.39297.
  20.  Rakieh C, Nam JL, Hunt L, et al. Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study. Ann Rheum Dis. 2015;74(9):1659-1666. doi:10.1136/annrheumdis-2014-205227.
  21.  Rose NR. Prediction and prevention of autoimmune disease in the 21st century: a review and preview. Am J Epidemiol. 2016;183(5):403-406. doi:10.1093/aje/kwv292.
  22.  Choi M, Fritzler M. Autoantibodies in SLE: prediction and the p value matrix. Lupus. 2019;28(11):1285-1293. doi:10.1177/0961203319868531.
  23.  Mu Q, Kirby J, Reilly CM, Luo XM. Leaky gut as a danger signal for autoimmune diseases. Front Immunol. 2017;8:598. doi:10.3389/fimmu.2017.00598.

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