insights

         Read time: 5 minutes

The prevalence of autoimmune disease, which collectively includes more than 80 conditions, has risen dramatically over the years, affecting more than 24 million people in the US¹ and an estimated one in ten people worldwide.² Genetics, infections, and changes in environmental exposures may play a role in the increasing number of cases.^1,3 To add to the complexity of the issue, large gender and racial disparities exist among different autoimmune diseases. Overall, the conditions disproportionately afflict women, 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).^4,5

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.^6,7 The detection of ANAs may indicate the future development of an autoimmune disease and may even precede symptoms by years.⁶ 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 existing or impending autoimmune disorder. A recent cross-sectional study investigated the prevalence of ANAs in the US over a 25-year span, from 1988 to 2012.⁶ Investigators used blood test results (serum ANA measured by standard indirect immunofluorescence (IIF) assays on human epithelial type 2 (HEp-2) cells) from 13,519 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 2011-2012.⁶ Results for each time period indicated the following ANA prevalence percentages and estimations of ANA-positive individuals:⁶

• 1988-1991: 11.0% (~22.3 million)
• 1999-2004: 11.4% (~26.6 million)
• 2011-2012: 16.1% (~41.5 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.⁶ Additional results from this study indicated that ANA prevalence specifically increased for:⁶

• 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.^8,9 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.¹⁰ A standard screening for ANA detection is the IIF assay on HEp-2 cells,^8,11,12 and an expanded profile of autoantibody testing may be available for some autoimmune conditions.¹³ 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.¹⁴

Studies have indicated autoantibodies as a potential predictor of conditions such as SLE, inflammatory bowel disease, type 1 diabetes, autoimmune skin disorders such as scleroderma, and rheumatoid arthritis (RA).^14-17 A 2015 cohort study investigated the positive predictive value (PPV) of autoantibodies for the development of RA in healthy relatives of patients with RA.¹⁵ 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.¹⁵

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.^16,18 In a clinical setting, ANA testing may present an opportunity to expand interventions that emphasize awareness and 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.¹⁹ 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).

Related Articles

Autoimmune Disease: Treatments and Outcomes

GENETIC PREDISPOSITION AND AUTOIMMUNE DISEASE

Windows of Opportunity for Preclinical Rheumatoid Arthritis

Type 1 Diabetes Prevention

References

1. National Institute of Environmental Health Sciences. Autoimmune diseases. Reviewed May 31, 2022. Accessed November 21, 2023. https://www.niehs.nih.gov/health/topics/conditions/autoimmune/index.cfm
2. Conrad N, Misra S, Verbakel JY, et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. Lancet. 2023;401(10391):1878-1890. doi:1016/S0140-6736(23)00457-9
3. National Institutes of Health. Marker of autoimmunity increases in the U.S. Published April 21, 2020. Accessed November 21, 2023. https://www.nih.gov/news-events/nih-research-matters/marker-autoimmunity-increases-us
4. 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:1016/j.autrev.2019.102423
5. Izmirly PM, Parton H, Wang L, et al. Prevalence of systemic lupus erythematosus in the United States: estimates from a meta-analysis of the Centers for Disease Control and Prevention National Lupus Registries. Arthritis Rheumatol. 2021;73(6):991-996. doi:1002/art.41632
6. Dinse GE, Parks CG, Weinberg CR, et al. Increasing prevalence of antinuclear antibodies in the United States. Arthritis Rheumatol. 2022;74(12):2032-2041. doi:1002/art.42330
7. Meier HCS, Sandler DP, Wilkerson J, Miller FW, Dinse GE, Parks CG. Hygiene hypothesis indicators and prevalence of antinuclear antibodies in US adolescents. Front Immunol. 2022;13:789379. doi:3389/fimmu.2022.789379
8. American College of Rheumatology. Antinuclear antibodies (ANA). Reviewed February 2023. Accessed November 21, 2023. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Antinuclear-Antibodies-ANA
9. Zanussi JT, Zhao J, Wei WQ, et al. Clinical diagnoses associated with a positive antinuclear antibody test in patients with and without autoimmune disease. BMC Rheumatol. 2023;7(1):24. doi:1186/s41927-023-00349-4
10.  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:1136/annrheumdis-2018-214819
11.  Bonroy C, Vercammen M, Fierz W, et al. Detection of antinuclear antibodies: recommendations from EFLM, EASI and ICAP. Clin Chem Lab Med. 2023;61(7):1167-1198. doi:1515/cclm-2023-0209
12.  Vercammen M, Bonroy C, Broeders S, et al. Analytical aspects of the antinuclear antibody test by HEp-2 indirect immunofluorescence: EFLM report on an international survey. Clin Chem Lab Med. 2023;61(7):1199-1208. doi:1515/cclm-2023-0210
13.  Almaabdi K, Ahmad Z, Johnson SR. Advanced autoantibody testing in systemic sclerosis. Diagnostics (Basel). 2023;13(5):851. doi:3390/diagnostics13050851
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:1515/cclm-2017-0241
15.  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:1002/art.39297
16.  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:1093/aje/kwv292
17.  Krischer JP, Liu X, Vehik K, et al. Predicting islet cell autoimmunity and type 1 diabetes: an 8-year TEDDY study progress report. Diabetes Care. 2019;42(6):1051-1060. doi:2337/dc18-2282
18.  Choi M, Fritzler M. Autoantibodies in SLE: prediction and the p value matrix. Lupus. 2019;28(11):1285-1293. doi:1177/0961203319868531
19.  Di Vincenzo F, Del Gaudio A, Petito V, Lopetuso LR, Scaldaferri F. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review. Intern Emerg Med. Published online July 28, 2023. doi:1007/s11739-023-03374-w