BEST PRACTICES :: BIOMARKERS


sociated with severe disease. PAD4 antibodies occur along with ACPA and can be found in 22%-45% of RA patients.23


Anti-BRAF


antibodies are present in 21%-32% of RA patients but have also been found in similar frequency in other autoimmune disorders indicating that anti-BRAF antibodies are not specific for RA.4


Conclusions and ongoing research As of 2021, several autoantibodies have been identified in RA, many of which are directed against post-translationally modified proteins. In 2010, the international classification criteria for RA recognized the importance of RF and ACPAs in identifying RA disease.5


The presence of RF and ACPA levels provides informa- tion about the disease course and gives other pathophysiologi- cal information. ACPA testing is highly sensitive for RA and has a high predictive value for disease onset and severity. The identification of antibodies other novel target antigens such as CEP-1, CarP, BRAF etc., may be useful as a complement to RF an ACPA testing.


RA management has been improved through disease-mod- ifying antirheumatic drugs (DMARDs). ACPA status predicts response to therapy and with treatment, ACPA titers have been shown to decrease. DMARD treatment has been found to cause a 25% or more reduction in ACPA in 50% of patients.24 Changes in RF in response to treatment has been previously demonstrated and research has shown that RF positivity predicts better response to rituximab and tocilizumab treatment.7,25


Still


more research is needed to demonstrate the usefulness of RF testing in treatment monitoring. As a small percentage of RA patients may be seronegative for the typical RA-associated antibodies, it is important for scientists to continue to search for new biomarkers in RA. As an early and accurate diagnosis is important for patient prognosis, routine testing for a spectrum of biomarkers is advisable so that RA cases are not missed.


REFERENCES


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2. Rheumatoid arthritis symptoms and treatments. @NHSinform. https:// www.nhsinform.scot/illnesses-and-conditions/muscle-bone-and-joints/ conditions/rheumatoid-arthritis. Published 2021. Accessed November 4, 2021.


3. Kavuncu V, Evcik D. Physiotherapy in rheumatoid arthritis. MedGenMed. 2004;6(2):3-3.


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5. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis clas- sification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569- 2581. doi: 10.1002/art.27584.


6. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti–cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146(11):797-808. doi: 10.7326/0003-4819-146-11-200706050-00008.


7. Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid Factors: clinical applications. Dis Markers. 2013;35(6):727-34. doi: 10.1155/2013/726598.


8. Song YW, Kang EH. Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. QJM. 2010;103(3):139-146. doi: 10.1093/qjmed/hcp165.


9. Nielen MMJ, van Schaardenburg D, Reesink HW, et al. Specific auto- antibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380-386. doi: 10.1002/art.20018.


3 DECEMBER 2021 MLO-ONLINE.COM 8


10. Coenen D, Verschueren P, Westhovens R, Bossuyt X. Technical and diagnostic performance of 6 assays for the measurement of citrullinated protein/peptide antibodies in the diagnosis of rheumatoid arthritis. Clin Chem. 2007;53(3):498-504. doi: 10.1373/clinchem.2006.078063.


11. Iwaszkiewicz C, Puszczewicz M, Białkowska-Puszczewicz G. Diagnostic value of the anti-Sa antibody compared with the anti-cyclic citrullinated peptide antibody in rheumatoid arthritis. Int J Rheum Dis. 2015;18(1):46-51. doi: 10.1111/1756-185X.12544.


12. Innala L, Kokkonen H, Eriksson C, Jidell E, Berglin E, Dahlqvst SR. Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides. J Rheumatol. 2008;35(6):1002-1008.


13. Silveira IG, Burlingame RW, von Mühlen CA, Bender AL, Staub HL. Anti-CCP antibodies have more diagnostic impact than rheumatoid factor (RF) in a population tested for RF. Clin Rheumatol. 2007;26(11):1883-1889. doi: 10.1007/s10067-007-0601-6.


14. Machold KP, Stamm TA, Nell VP, et al. Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology (Oxford). 2007;46(2):342-349. doi: 10.1093/rheumatology/kel237.


15. Sokolove J, Johnson DS, Lahey LJ, et al. Rheumatoid factor as a potentiator of anti–citrullinated protein antibody–mediated inflammation in rheumatoid arthritis. Arthritis Rheumatol. 2014;66(4):813-821. doi: 10.1002/ art.38307.


16. Reichert S, Schlumberger W, Dähnrich C, et al. Association of levels of antibodies against citrullinated cyclic peptides and citrullinated -enolase in chronic and aggressive periodontitis as a risk factor of Rheumatoid arthritis: a case control study. J Transl Med. 2015;13(1):283. doi: 10.1186/ s12967-015-0625-7.


17. Lundberg K, Kinloch A, Fisher BA, et al. Antibodies to citrullinated -enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 2008;58(10):3009-3019. doi: 10.1002/ art.23936.


18. Liu Y, Liu C, Li L, Zhang F, Li Y, Zhang S. High levels of antibodies to citrullinated -enolase peptide-1 (CEP-1) identify erosions and interstitial lung disease (ILD) in a Chinese rheumatoid arthritis cohort. Clin Immunol. 2019;200:10-15. doi: 10.1016/j.clim.2019.01.001.


19. Mahdi H, Fisher BA, Källberg H, et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat Genet. 2009;41(12):1319-1324. doi: 10.1038/ng.480.


20. Carubbi F, Alunno A, Gerli R, Giacomelli R. Post-Translational Modifica- tions of Proteins: Novel Insights in the Autoimmune Response in Rheumatoid Arthritis. Cells. 2019;8(7):657. doi: 10.3390/cells8070657.


21. Shi J, Knevel R, Suwannalai P, et al. Autoantibodies recognizing carba- mylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci U S A. 2011;108(42):17372-17377. doi: 10.1073/pnas.1114465108.


22. Scinocca M, Bell DA, Racapé M, et al. Antihomocitrullinated fibrinogen antibodies are specific to rheumatoid arthritis and frequently bind citrul- linated proteins/peptides. J Rheumatol. 2014;41(2):270-279. doi: 10.3899/ jrheum.130742.


23. Demoruelle MK, Wang H, Davis RL, et al. Anti-peptidylarginine deimi- nase-4 antibodies at mucosal sites can activate peptidylarginine deiminase-4 enzyme activity in rheumatoid arthritis. Arthritis Res Ther. 2021;23(1):163. doi: 10.1186/s13075-021-02528-5.


24. Mikuls TR, O’Dell JR, Stoner JA, et al. Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti–cyclic citrullinated peptide antibody. Arthritis Rheum. 2004;50(12):3776-3782. doi: 10.1002/art.20659.


25. Maneiro RJ, Salgado E, Carmona L, Gomez-Reino JJ. Rheumatoid fac- tor as predictor of response to abatacept, rituximab and tocilizumab in rheumatoid arthritis: Systematic review and meta-analysis. Semin Arthritis Rheum. 2013;43(1):9-17. doi: 10.1016/j.semarthrit.2012.11.007.


Ilana Heckler, PhD, is the Scientific Affairs Associate at EUROIMMUN US. In this role, she supports scientific collaborations and assists in the validation of diagnostic assays for autoimmunity and infectious diseases.


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