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Limitations of Diagnostics for Autoimmune Disease Biomarkers

Jan 19, 2022 11:00:00 AM / by Karolina Künnapuu

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Dysfunction of the immune system can lead to autoimmune disease, in which the body’s defence systems target its own tissues. Over 80 autoimmune diseases have been identified to date and an estimated 5-8% of the world’s population suffers from an autoimmune disease (1), causing socioeconomic strain (2) and arousing an urgent need for prompt detection and treatment of these diseases.

 

Unfortunately, the aetiology of autoimmune diseases is not entirely clear and indicators of disease are shared across various autoimmune diseases, making diagnosis and treatment difficult. The greatest limitation of currently available diagnostic tests is that they lack sensitivity and/or specificity, which means patients endure a variety of laboratory tests, symptom evaluation and tests like ultrasound and tissue biopsies before healthcare providers can arrive at a diagnosis (3).

 

Extensive testing can be cost- and time-intensive and is stressful for the patient. Improving on the limitations of tests that are currently in use would lead to autoimmune diseases being diagnosed more quickly and conveniently and allow for more effective treatment, slowing disease development and raising patients’ quality of life.

 

Karolina - Limitations of diagnostics of AD biomarkers fig 1

Figure 1: Examples of autoimmune diseases affecting different organ systems (4)

 

 

Biomarkers of inflammation

Autoimmune diseases are associated with changes in the serum levels of various inflammatory proteins, such as C-reactive protein (CRP), fibrinogen, ferritin and haptoglobin (4), meaning that tests that detect the presence of these proteins can be used to detect signs of immune system dysfunction. A change in inflammatory serum protein levels, however, is not specific to autoimmune disease and is simply an indicator of the presence of inflammation. An increase in ferritin, for example, is associated with juvenile arthritis, but also iron overload diseases (5).

 

The presence of inflammatory biomarkers is thus rarely reason enough to diagnose a patient with an autoimmune disease. Furthermore, the levels of inflammatory proteins indicated by these tests may not accurately reflect a patient’s disease status. One study found that 44% of rheumatoid arthritis (RA) patients in Jyväskylä, Finland, and 58% of RA patients in Nashville, United States, had CRP levels under the disease threshold of 10mg/L (6). This suggests that the sensitivity of the tests is not ideal.

 

 

Antinuclear antibody (ANA) test

An antinuclear antibody (ANA) test is commonly the first-line diagnostic test upon suspicion of autoimmune disease, particularly systemic lupus erythematosus (SLE) and rheumatic diseases. ANAs are a group of autoantibodies that associate with components of the cell nucleus. Some ANAs are associated with specific autoimmune diseases, while others are elevated in various diseases (5). ANA presence can be detected through analysis of a variety of ANA assays, including immunofluorescence, ELISA, and multiplex assays.

 

Although widely used as a diagnostic test, ANA assays are associated with disadvantages that make diagnosis challenging. Not only do up to 20-30% of healthy individuals falsely test positive for an ANA, but false-negative results among people with autoimmune disease are also relatively common and some disease biomarker autoantibodies, such as those for myositis, may not be detected using certain ANA assays (7). The reason for the high number of positive tests in healthy people is not known, but possible reasons involve cross-reactivity and binding to protein DFS70, which is commonly present in healthy individuals (7). Due to ANA tests’ unreliable results, further testing is frequently needed in addition to further symptom evaluation to reach a diagnosis. Even so, incorrect diagnoses based on ANA results are not uncommon (8).

 

 

Other autoantibody tests

Rheumatoid factor (RF) and antibodies against cyclic citrulline peptide (CCP) are also frequently tested for in suspected autoimmune disease patients. While commonly associated with rheumatoid arthritis, elevated levels of these two autoantibodies are also present in other autoimmune diseases (e.g. Sjögren’s syndrome, lupus) as well as some infectious and pulmonary diseases (5). Interpreting test results is also made difficult by the fact that autoimmune diseases present differently in different individuals; some patients may test positive for both anti-CCP antibodies and RF, while others may only test positive for one or the other (9). RF and anti-CCP tests have similar sensitivity (around 50-70%), while anti-CCP tests have higher specificity (95% as opposed to 85% for RF) (10). While autoantibody assays can be useful in determining the presence of disease biomarkers in the body, the fact that these biomarkers are absent in many patients (10) means that testing must always be combined with an evaluation of other potential signs of disease as a negative test result may not be reliable.

 

 

Conclusion

Although various biomarkers for autoimmune diseases exist, testing for autoimmune diseases can be a time and resource-demanding process. Currently available assays lack either sensitivity and specificity and extensive testing in addition to symptom evaluation are often needed to reach a reliable diagnosis. Improved diagnostic tests that exhibit both sensitivity and specificity would reduce the time and cost of diagnosing autoimmune diseases, allowing diseases to be detected early and making treatment more effective.

 

 

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References

  1. Fugger, L., Jensen, L.T. and Rossjohn, J. (2020) ‘Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases’, Cell, 181(1), pp. 63–80.
  2. Blaabjerg, M., Seifert-Held, T. and Sellner, J. (2019) ‘Editorial: Emerging Challenges in the Diagnosis and Treatment of Autoimmune Encephalitis’, Frontiers in Neurology, 10, p. 146.
  3. Autoimmune Diseases | Diagnosis & Treatment | Boston Children’s Hospital (no date). Available at: https://www.childrenshospital.org/conditions-and-treatments/conditions/a/autoimmune-diseases/diagnosis-and-treatment (Accessed: 12 December 2022).
  4. Wang, L., Wang, F.-S. and Gershwin, M.E. (2015) ‘Human autoimmune diseases: a comprehensive update’, Journal of Internal Medicine, 278(4), pp. 369–395.
  5. Castro, C. and Gourley, M. (2010) ‘Diagnostic Testing and Interpretation of Tests for Autoimmunity’, The Journal of allergy and clinical immunology, 125(2 Suppl 2), pp. S238–S247.
  6. Sokka, T. and Pincus, T. (2009) ‘Erythrocyte Sedimentation Rate, C-Reactive Protein, or Rheumatoid Factor Are Normal at Presentation in 35%–45% of Patients with Rheumatoid Arthritis Seen Between 1980 and 2004: Analyses from Finland and the United States’, The Journal of Rheumatology, 36(7), pp. 1387–1390.
  7. Pisetsky, D. 2017. Antinuclear antibody testing — misunderstood or misbegotten?. Nat Rev Rheumatol 13, pp. 495–502.
  8. Bossuyt, X. et al. (2020) ‘Understanding and interpreting antinuclear antibody tests in systemic rheumatic diseases’, Nature Reviews Rheumatology, 16(12), pp. 715–726.
  9. Niewold, T.B., Harrison, M.J., Paget, S.A. 2007. Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis, QJM: An International Journal of Medicine, 100(4), pp. 193–201.
  10. Braschi, E., Shojania, K., & Allan, G. M. (2016). Anti-CCP: a truly helpful rheumatoid arthritis test?. Canadian family physician Medecin de famille canadien, 62(3), p. 234.

 

 

Tags: Point of Care

Karolina Künnapuu

Written by Karolina Künnapuu

Karolina has a background in Pharmacology