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Reliable and cost-effective serodiagnosis of rheumatoid arthritis

  • Review Article - Biomarkers
  • Published:
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Abstract

Early diagnosis of patients with rheumatoid arthritis (RA) optimises therapeutic benefit and the probability of achieving disease remission. Notwithstanding clinical acumen, early diagnosis is dependent on access to reliable serodiagnostic procedures, as well as on the discerning application and interpretation of these. In the case of RA, however, no disease-specific serodiagnostic procedure is available due to the multi-factorial and polygenic nature of this autoimmune disorder. This has resulted in the development of an array of serodiagnostic procedures based on the detection of autoantibodies reactive with various putative autoantigens. Other procedures based on measurement of elevations in the concentrations of systemic biomarkers of inflammation, most commonly acute phase reactants and cytokines/chemokines, are used as objective indices of disease activity. Following a brief overview of RA research in African populations, the current review is focused on those autoantibodies/biomarkers, specifically rheumatoid factor, anti-citrullinated peptide antibodies and C-reactive protein, which are currently recognised as being the most reliable and cost-effective with respect to disease prediction and diagnosis, as well as in monitoring activity and outcome.

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Abbreviations

ACPAs:

Anti-citrullinated peptide antibodies

CRP:

C-reactive protein

Ig:

Immunoglobulin

RF:

Rheumatoid factor

DAS:

Disease activity score

SDAI:

Simplified Disease Activity Index

DMARD:

Disease-modifying anti-rheumatic drug

References

  1. Ifad (2011) Rural poverty report 2011 [Electronic Report] Rome, Italy. www.ifad.org [cited 2015 13 July]. http://www.ifad.org/rpr2011/report/e/overview.pdf

  2. Pugner KM, Scott DI, Holmes JW, Hieke K (2000) The costs of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum 29(5):305–320

    Article  CAS  PubMed  Google Scholar 

  3. Behzad H (2011) Rheumatoid arthritis: early diagnosis and treatment outcomes. Casp J Intern Med 2(1):161–170

    Google Scholar 

  4. Radner H, Smolen JS, Aletaha D (2014) Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs. Arthritis Res Ther 16(1):R56

    Article  PubMed  PubMed Central  Google Scholar 

  5. Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P et al (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75(1):3–15

    Article  PubMed  PubMed Central  Google Scholar 

  6. Meyer PWA, Hodkinson B, Mahmood A, Musenge E, Wadee AA, Fickl H et al (2010) Circulating cytokine profiles and their relationship with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Mediat Inflamm, Article ID 158154. doi:10.1155/2010/158514

  7. Meyer PW, Hodkinson B, Ally M, Musenge E, Wadee AA, Fickl H et al (2011) HLA-DRB1 shared epitope genotyping using the revised classification and its association with circulating autoantibodies, acute phase reactants, cytokines and clinical indices of disease activity in a cohort of South African rheumatoid arthritis patients. Arthritis Res Ther 13(5):R160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ally MM, Hodkinson B, Meyer PW, Musenge E, Tikly M, Anderson R (2013) Serum matrix metalloproteinase-3 in comparison with acute phase proteins as a marker of disease activity and radiographic damage in early rheumatoid arthritis. Mediat Inflamm 2013:183653

    Article  Google Scholar 

  9. May A, Hazelhurst S, Li Y, Norris SA, Govind N, Tikly M et al (2013) Genetic diversity in black South Africans from Soweto. BMC Genom 14(1):1–12

    Article  Google Scholar 

  10. Govind N, Choudhury A, Hodkinson B, Ickinger C, Frost J, Lee A et al (2014) Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in Black South Africans. Mol Med 20(1):341–349

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ally MM, Hodkinson B, Meyer PW, Musenge E, Tintinger GR, Tikly M et al (2015) Circulating anti-citrullinated peptide antibodies, cytokines and genotype as biomarkers of response to disease-modifying antirheumatic drug therapy in early rheumatoid arthritis. BMC Musculoskelet Disord 16:130

    Article  PubMed  PubMed Central  Google Scholar 

  12. Nam J, Villeneuve E, Emery P (2009) The role of biomarkers in the management of patients with rheumatoid arthritis. Curr Rheumatol Rep 11(5):371–377

    Article  CAS  PubMed  Google Scholar 

  13. Curtis JR, Van Der Helm-Van Mil AH, Knevel R, Huizinga TW, Haney DJ, Shen Y et al (2012) Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res 64(12):1794–1803

    Article  Google Scholar 

  14. Trouw LA, Mahler M (2012) Closing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis. Autoimmun Rev 12(2):318–322

    Article  CAS  PubMed  Google Scholar 

  15. Centola M, Cavet G, Shen Y, Ramanujan S, Knowlton N, Swan KA et al (2013) Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS ONE 8(4):e60635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Burska A, Boissinot M, Ponchel F (2014) Cytokines as biomarkers in rheumatoid arthritis. Mediat Inflamm 2014:24

    Google Scholar 

  17. Michaud K, Strand V, Shadick NA, Degtiar I, Ford K, Michalopoulos SN et al (2015) Outcomes and costs of incorporating a multibiomarker disease activity test in the management of patients with rheumatoid arthritis. Rheumatology (Oxford) 54(9):1640–1649

    Article  Google Scholar 

  18. Dowman B, Campbell RM, Zgaga L, Adeloye D, Chan KY (2012) Estimating the burden of rheumatoid arthritis in Africa: a systematic analysis. J Glob Health 2(2):020406

    Article  PubMed  PubMed Central  Google Scholar 

  19. Owino BO, Oyoo GO, Otieno CF (2009) Socio-demographic and clinical aspects of rheumatoid arthritis. East Afr Med J 86(5):204–211

    CAS  PubMed  Google Scholar 

  20. Parker R, Jelsma J (2010) The prevalence and functional impact of musculoskeletal conditions amongst clients of a primary health care facility in an under-resourced area of Cape Town. BMC Musculoskelet Disord 11:2

    Article  PubMed  PubMed Central  Google Scholar 

  21. Singwe-Ngandeu M, Finckh A, Bas S, Tiercy JM, Gabay C (2010) Diagnostic value of anti-cyclic citrullinated peptides and association with HLA-DRB1 shared epitope alleles in African rheumatoid arthritis patients. Arthritis Res Ther 12(2):R36

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hodkinson B, Meyer PW, Musenge E, Ally MM, Wadee AA, Anderson R et al (2010) The diagnostic utility of the anti-CCP antibody test is no better than rheumatoid factor in South Africans with early rheumatoid arthritis. Clin Rheumatol 29(6):615–618

    Article  PubMed  Google Scholar 

  23. Hodkinson B, Musenge E, Ally M, Meyer PW, Anderson R, Tikly M (2011) Response to traditional disease-modifying anti-rheumatic drugs in indigent South Africans with early rheumatoid arthritis. Clin Rheumatol 31:613–619

    Article  PubMed  Google Scholar 

  24. Hodkinson B, Meyer PW, Musenge E, Ally M, Anderson R, Tikly M (2012) Exaggerated circulating Th-1 cytokine response in early rheumatoid arthritis patients with nodules. Cytokine 60(2):561–564

    Article  CAS  PubMed  Google Scholar 

  25. Tezenas Du Montcel S, Michou L, Petit-Teixeira E, Osorio J, Lemaire I, Lasbleiz S et al (2005) New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility. Arthritis Rheum 52(4):1063–1068

    Article  CAS  Google Scholar 

  26. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III et al (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581

    Article  PubMed  Google Scholar 

  27. Renaudineau Y, Jamin C, Saraux A, Youinou P (2005) Rheumatoid factor on a daily basis. Autoimmunity 38(1):11–16

    Article  CAS  PubMed  Google Scholar 

  28. Food US, Drug A (1997) Review criteria for assessment of rheumatoid factor (Rf) in vitro diagnostic devices using enzyme-linked immunoassay (Eia), enzyme linked immunosorbent assay (Elisa), particle agglutination tests, and laser and rate nephelometry. FDA

  29. Van Boekel MA, Vossenaar ER, Van Den Hoogen FH, Van Venrooij WJ (2002) Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Res 4(2):87–93

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ingegnoli F, Castelli R, Gualtierotti R (2013) Rheumatoid factors: clinical applications. Dis Markers 35(6):727–734

    Article  PubMed  PubMed Central  Google Scholar 

  31. Valesini G, Alessandri C (2009) Anticitrullinated protein/peptide antibodies and rheumatoid factors: two distinct autoantibody systems. Arthritis Res Ther 11(5):125. doi:10.1186/ar2786

    Article  PubMed  PubMed Central  Google Scholar 

  32. Steiner G, Smolen JS (2002) Autoantibodies in rheumatoid arthritis and their clinical significance. Arthritis Res 4(Suppl 2):S1–S5

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jonsson T, Steinsson K, Jonsson H, Geirsson AJ, Thorsteinsson J, Valdimarsson H (1998) Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis. Rheumatol Int 18(3):119–122

    Article  CAS  PubMed  Google Scholar 

  34. Schellekens GA, Visser H, BaW De Jong, Van Den Hoogen FHJ, Hazes JMW, Breedveld FC et al (2000) The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43(1):155–163

    Article  CAS  PubMed  Google Scholar 

  35. Vossenaar ER, Zendman AJ, Van Venrooij WJ, Pruijn GJ (2003) PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. BioEssays News Rev Mol Cell Dev Biol 25(11):1106–1118

    Article  CAS  Google Scholar 

  36. Rantapää-Dahlqvist S (2005) Diagnostic and prognostic significance of autoantibodies in early rheumatoid arthritis. Scand J Rheumatol 24:83–96

    Article  Google Scholar 

  37. Aggarwal R, Liao K, Nair R, Ringold S, Costenbader KH (2009) Anti-citrullinated peptide antibody (ACPA) assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Rheum 61(11):1472–1483

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rantapää-Dahlqvist S, Boman K, Tarkowski A, Hallmans G (2007) Up regulation of monocyte chemoattractant protein-1 expression in anti-citrulline antibody and immunoglobulin M rheumatoid factor positive subjects precedes onset of inflammatory response and development of overt rheumatoid arthritis. Ann Rheum Dis 66(1):121–123

    Article  PubMed  PubMed Central  Google Scholar 

  39. Infantino M, Manfredi M, Meacci F, Sarzi-Puttini P, Ricci C, Atzeni F et al (2014) Anti-citrullinated peptide antibodies and rheumatoid factor isotypes in the diagnosis of rheumatoid arthritis: an assessment of combined tests. Clin Chim Acta 436:237–242

    Article  CAS  PubMed  Google Scholar 

  40. Hou YF, Sun GZ, Sun HS, Pan WP, Liu WB, Zhang CQ (2012) Diagnostic value of anti-Sa and anticitrullinated protein antibodies in rheumatoid arthritis. J Rheumatol 39(8):1506–1508

    Article  CAS  PubMed  Google Scholar 

  41. El-Gabalawy HS, Wilkins JA (2004) Anti-Sa antibodies: prognostic and pathogenetic significance to rheumatoid arthritis. Arthritis Res Ther 6(2):86–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Skriner K, Sommergruber WH, Tremmel V, Fischer I, Barta A, Smolen JS et al (1997) Anti-A2/RA33 autoantibodies are directed to the RNA binding region of the A2 protein of the heterogeneous nuclear ribonucleoprotein complex—differential epitope recognition in rheumatoid arthritis, systemic lupus erythematosus, and mixed connective tissue disease. J Clin Investig 100(1):127–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Luime JJ, Colin EM, Hazes JMW, Lubberts E (2010) Does anti-mutated citrullinated vimentin have additional value as a serological marker in the diagnostic and prognostic investigation of patients with rheumatoid arthritis? A systematic review. Ann Rheum Dis 69(2):337–344

    Article  CAS  PubMed  Google Scholar 

  44. Otterness IG (1994) The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum 24(2):91–104

    Article  CAS  PubMed  Google Scholar 

  45. Nielen MMJ, Van Schaardenburg D, Reesink HW, Twisk JWR, Van De Stadt RJ, Van Der Horst-Bruinsma IE et al (2004) Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis. Arthritis Rheum 50(8):2423–2427

    Article  CAS  PubMed  Google Scholar 

  46. Listing J, Rau R, Muller B, Alten R, Czerwony G, Gromnica-Ihle E (2000) HLA-DRB1 genes, rheumatoid factor, and elevated C-reactive protein: independent risk factors of radiographic progression in early rheumatoid arthritis. J Rheumatol 27(9):2100–2109

    CAS  PubMed  Google Scholar 

  47. Yamane T, Hashiramoto A, Tanaka Y, Tsumiyama K, Miura Y, Shiozawa K et al (2008) Easy and accurate diagnosis of rheumatoid arthritis using anti-cyclic citrullinated peptide 2 antibody, swollen joint count, and C-reactive protein/rheumatoid factor. J Rheumatol 35(3):414–420

    CAS  PubMed  Google Scholar 

  48. Taylor P, Gartemann J, Hsieh J, Creeden J (2011) A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis. Autoimmune Dis, Article ID 815038. doi:10.4061/2011/815038

  49. Saulot V, Vittecoq O, Charlionet R, Fardellone P, Lange C, Marvin L et al (2002) Presence of autoantibodies to the glycolytic enzyme alpha-enolase in sera from patients with early rheumatoid arthritis. Arthritis Rheum 46(5):1196–1201

    Article  CAS  PubMed  Google Scholar 

  50. Harris ML, Darrah E, Lam GK, Bartlett SJ, Giles JT, Grant AV et al (2008) Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis. Arthritis Rheum 58(7):1958–1967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology, Faculty of Health Sciences, University of Pretoria, Prinshof Campus, 5 Bophelo Rd, PO Box X323, Pretoria, South Africa

    Pieter W. A. Meyer & Ronald Anderson

  2. Tshwane Academic Division, National Health Laboratory Service, PO Box X323, Pretoria, 0001, South Africa

    Pieter W. A. Meyer

  3. Department Internal Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, 9th Floor Steve Biko Academic Hospital, Dr Savage Road, Pretoria, 0002, South Africa

    Mahmood M. T. M. Ally

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  1. Pieter W. A. Meyer
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Correspondence to Pieter W. A. Meyer.

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Meyer, P.W.A., Ally, M.M.T.M. & Anderson, R. Reliable and cost-effective serodiagnosis of rheumatoid arthritis. Rheumatol Int 36, 751–758 (2016). https://doi.org/10.1007/s00296-016-3433-3

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