Skip to main content
PMC home page
Journal of Clinical Laboratory Analysis logoLink to Journal of Clinical Laboratory Analysis
. 2001 Mar 13;14(6):305–313. doi: 10.1002/1098-2825(20001212)14:6<305::AID-JCLA10>3.0.CO;2-P

Progress in the use of biochemical and biological markers for evaluation of rheumatoid arthritis

Robert M Nakamura 1,✉
PMCID: PMC6808153  PMID: 11138614

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disorder which is predominant in females. The exact etiology remains undefined.

Recently, a large number of biochemical and biologic markers, which are useful in the diagnosis, prognosis, and monitoring therapy of RA, have been reported. The new markers include genetic markers, filaggrin, citrulline containing peptides, A2/RA 33, cytokines, joint and collagen breakdown products, and bone turnover markers. No laboratory tests in and of themselves are diagnostic of RA. The new markers have been employed in monitoring RA patients during treatment and following the course of the disease. With the development of innovative therapies for RA, many of the biochemical and biologic markers will be useful. J. Clin. Lab. Anal. 14:305–313, 2000. © 2000 Wiley‐Liss, Inc.

Keywords: rheumatoid arthritis, biochemical, biological and genetic markers, laboratory tests

REFERENCES

  • 1. Wolfe AM. 1968. The epidemiology of rheumatoid arthritis: a review. II. Incidence and diagnostic criteria. Bull Rheum Dis 19:524–529. [PubMed] [Google Scholar]
  • 2. Harris ED Jr. 1993. Etiology and pathogenesis of rheumatoid arthritis In: Kelly W, Harris ED Jr, Ruddy Sl, Sledge CB, editors. Textbook of rheumatology, Vol. 1, 4th ed. Philadelphia: W.B. Saunders; Chap 51. p 833–868. [Google Scholar]
  • 3. Harris ED Jr. 1993. Clinical features of rheumatoid arthritis In: Kelly W, Harris ED Jr, Ruddy Sl, Sledge CB, editors. Textbook of rheumatology. Vol. 1, 4th ed. Philadelphia: W.B. Saunders; Chap 52. p 874–907. [Google Scholar]
  • 4. Kavanaugh AF, Lipsky PE. 1996. Rheumatoid arthritis In: Rich RR, Fleisher TA, Shearer WT, Schwartz BD, Strober W, editors. Clinical immunology: principles and practice. St Louis, MO: Mosby & Co. Chap. 72. p 1093–1116. [Google Scholar]
  • 5. Persellin RH. 1977. The effect of pregnancy on rheumatoid arthritis. Bull Rheum Dis 27:922–927. [PubMed] [Google Scholar]
  • 6. Ropes MW, Benett EA, Cobb S, Jacox R, Jessor R. 1958. 1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175–176. [PubMed] [Google Scholar]
  • 7. Arnett FC, Edworthy SM, Block DA, et al. 1988. Classification of rheumatoid arthritis. Arthritis Rheum 31:315–324. [DOI] [PubMed] [Google Scholar]
  • 8. Weyand CM, Goronzy JJ. 1997. Pathogenesis of rheumatoid arthritis. Med Clin N Am 81:29–55. [DOI] [PubMed] [Google Scholar]
  • 9. Arend WP, Dayer JM. 1995. Inhibition of the production and effects of interleukin‐1 and tumor necrosis factor α in rheumatoid arthritis. Arthritis Rheum 38:151–160. [DOI] [PubMed] [Google Scholar]
  • 10. Wallis WJ, Furst DE, Strand V, Keystone E. 1998. Biologic agents and immunotherapy in rheumatoid arthritis. Rheum Dis Clin N Am 24(3):537–565. [DOI] [PubMed] [Google Scholar]
  • 11. Moreland LW. 1998. Soluble tumor necrosis factor receptor (p75) fusion protein (Enbrel) as a therapy for rheumatoid arthritis. Rheum Dis Clin N Am 24(3):579–591. [DOI] [PubMed] [Google Scholar]
  • 12. Kavanaugh AF. 1998. Anti‐tumor necrosis factor α monoclonal antibody therapy for rheumatoid arthritis. Rheum Dis Clin N Am 24(3):593–614. [DOI] [PubMed] [Google Scholar]
  • 13. Bresnihan B, Cunnane G. 1998. Interleukin‐1 receptor antagonist. Rheum Dis Clin N Am 24(3):615–628. [DOI] [PubMed] [Google Scholar]
  • 14. Evans CH, Robbins PD. 1996. Pathways to gene therapy in rheumatoid arthritis. Curr Opin Rheumatol 8:230–234. [DOI] [PubMed] [Google Scholar]
  • 15. Evans CH, Ghivizzani SC, Kang R, Muzzonigro T, Wasko MC, Herndon JH, Robbins PD. 1999. Gene therapy for rheumatic diseases. Arthritis Rheum 42:1–16. [DOI] [PubMed] [Google Scholar]
  • 16. Keystone E, Wherry J, Grint P. 1998. IL‐10 as a therapeutic strategy in the treatment of rheumatoid arthritis. Rheum Dis Clin N Am 24(3):629–639. [DOI] [PubMed] [Google Scholar]
  • 17. Trentham DE. 1998. Oral tolerization as a treatment of rheumatoid arthritis. Rheum Dis Clin N Am 24(3):525–538. [DOI] [PubMed] [Google Scholar]
  • 18. Barland P, Lipstein E. 1996. Selection and use of laboratory tests in the rheumatic diseases. Am J Med 100(Suppl 2A):16S–23S. [DOI] [PubMed] [Google Scholar]
  • 19. Aho K, Palusuo T, Kurki P. 1994. Marker antibodies of rheumatoid arthritis: diagnostic and pathogenetic implications. Semin Arthritis Rheum 23:379–387. [DOI] [PubMed] [Google Scholar]
  • 20. Wollheim FA. 1996. Established and new biochemical tools for diagnosis and monitoring of rheumatoid arthritis. Curr Opin Rheumatol 8:221–225. [DOI] [PubMed] [Google Scholar]
  • 21. Weyand CM, Hicok KC, Conn DL, Goronzy JJ. 1992. The influence of HLA‐DRAB1 genes on disease severity in rheumatoid arthritis. Ann Int Med 117:801–806. [DOI] [PubMed] [Google Scholar]
  • 22. Weyand CM, McCarthy TG, Goronzy JJ. 1995. Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis. J Clin Invest 95:2120–2126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Arnett FC. 1994. Histocompatibility typing in the rheumatic diseases. Diagnostic and prognostic implications. Rheum Dis Clin N Am 20(2):371–390. [PubMed] [Google Scholar]
  • 24. Hall FC, Weeks DE, Camilleri JP, et al. 1996. Influence of the HLA‐DRB1 locus on susceptibility and severity in rheumatoid arthritis. Q J Med 89:821–829. [DOI] [PubMed] [Google Scholar]
  • 25. Gough A, Faint J, Salmon M, et al. 1994. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum 37: 1166–1170. [DOI] [PubMed] [Google Scholar]
  • 26. Shaw MA, Clayton D, Blackwell JM. 1997. Analysis of the candidate gene NRAMP1 in the first 61 ARC National Repository Families for Rheumatoid Arthritis. J Rheumatol 24(1):212–214. [PubMed] [Google Scholar]
  • 27. Waaler E. 1940. On the occurrence of a factor in human serum activating the specific agglutination of a sheep blood corpuscles. Acta Pathol Microbial Scand 17:122–188. [DOI] [PubMed] [Google Scholar]
  • 28. Chen PP, Fong S, Carson DA. 1987. Rheumatoid factor. Rheum Dis Clin N Am 13:545–568. [PubMed] [Google Scholar]
  • 29. Dorner RW, Alexander RL Jr, Moore TL. 1987. Rheumatoid factors. Clin Chem Acta 167:1–21. [DOI] [PubMed] [Google Scholar]
  • 30. Valdimarsson H, Jonsson T. 1996. Predictive value of rheumatoid factor isotypes for radiological progression in patients with rheumatoid arthritis [letter; comment]. Scand J Rheumatol 25(3):189–190. [DOI] [PubMed] [Google Scholar]
  • 31. Houssien DA, Jonsson T, Davies E, Scott DL. 1998. Rheumatoid factor isotypes, disease activity and the outcome of rheumatoid arthritis. Scand J Rheumatol 27:46–53. [DOI] [PubMed] [Google Scholar]
  • 32. Jonsson T, Steinsson K, Jonsson H, Geirsson A, Thorsteinsson J, Valdimarsson H. 1996. Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis (abstr). Scand J Immunol 43:739. [DOI] [PubMed] [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. Rheum Int 18(3):119–122. [DOI] [PubMed] [Google Scholar]
  • 34. Jonsson T, Thorsteinsson H, Arinbjarnarson S, Thorsteinsson J, Valdimarsson H. 1995. Clinical implications of IgA rheumatoid factor subclasses. Ann Rheum Dis 54:578–581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Thompson PW, Carr A. 1998. What about IgA rheumatoid factor in rheumatoid arthritis? Ann Rheum Dis 57:63–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Carson DA. Rheumatoid factor In: Kelly W, Harris ED Jr, Ruddy Sl, Sledge CB, editors. Textbook of rheumatology8. Vol. 1, 4th ed. Philadelphia: W.B. Saunders; Chap 8. p 155–163. [Google Scholar]
  • 37. Meltzer M, Franklin EC, Elias K, McCluskey KJ, Cooper M. 1966. Cryoglobulinemia: a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 40:837–856. [DOI] [PubMed] [Google Scholar]
  • 38. Scott DEI, Bacon TA, Allen C, Elson CJ, Wallington T. 1981. IgG rheumatoid factor, complement and immune complexes in rheumatoid synovitis, and vasculitis: comparative and serial studies during cytotoxic therapy. Clin Exp Immunol 43:54–63. [PMC free article] [PubMed] [Google Scholar]
  • 39. Tan EM. 1989. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 44:93–151. [DOI] [PubMed] [Google Scholar]
  • 40. Tan EM, Chan EKL, Sullivan KF, Rubin RL. 1988. Antinuclear antibodies (ANAs): diagnostically specific immune markers and clues toward the understanding of systemic autoimmunity. Clin Immunol Immunopathol 47:121–141. [DOI] [PubMed] [Google Scholar]
  • 41. Venables PJ, Pawlowski T, Mumford PA, Brown C, Crawford DH, Maini RN. 1988. Reaction of antibodies to rheumatoid arthritis nuclear antigen with a synthetic peptide corresponding to part of Epstein‐Barr nuclear antigen 1. Ann Rheum Dis 47:270–179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Aitcheson CT, Peebles C, Joslin F, Tan EM. 1980. Characteristics of antinuclear antibodies in rheumatoid arthritis. Arth Rheum 23:528. [DOI] [PubMed] [Google Scholar]
  • 43. Craft J, Harden JA. Antinuclear antibodies In: Kelly W, Harris ED Jr, Ruddy S, Sledge CB, editors. Textbook of rheumatology. Vol 1, 4th ed. Philadelphia: W.B. Saunders; 1993, ; Chap 9. p 164–187. [Google Scholar]
  • 44. Maleson P, Petty RE, Fung M, Candido EP. 1989. Reactivity of antinuclear antibodies with histones and other antigens in juvenile rheumatoid arthritis. Arthritis Rheum 32:919–923. [PubMed] [Google Scholar]
  • 45. Monestier M, Losman JA, Fasy TM, et al. 1990. Antihistone antibodies in antinuclear antibody‐positive juvenile arthritis. Arthritis Rheum 33:1836–1841. [DOI] [PubMed] [Google Scholar]
  • 46. Nakamura RM, Tan EM. 1992. Update on autoantibodies to intracellular antigens in systemic rheumatic diseases. Clin Lab Med 12:1–23. [PubMed] [Google Scholar]
  • 47. Sebbag M, Simon M, Vincent C, et al. 1995. The antiperinuclear factor and the so‐called antikeratin antibodies are the same rheumatoid arthritis‐specific autoantibodies. J Clin Invest 95:2672–2679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Nienhuis RLF, Mandema EA. 1964. A new serum factor in patients with rheumatoid arthritis. The antiperinuclear factor. Ann Rheum Dis 23:302–305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Hoet RM, Venrooij V. 1992. In: Smoker J, Kalden J, Maini RM, editors. Rheumatoid arthritis. Berlin: Springer‐Verlag; p 299–318. [Google Scholar]
  • 50. Munoz‐Fernandez S, Alvarez‐Doforno R, Fontan G, Euon J. 1995. Antiperinuclear factor isotypes in rheumatoid arthritis. Clin Exp Rheumatol 13:529–536. [PubMed] [Google Scholar]
  • 51. Young BJJ, Mallya RK, Leslie RDG, Hamblin TJ, Clark CJM. 1979. Antikeratin antibodies in rheumatoid arthritis. Br Med J 2:97–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Schellekens GA, de Jong BAW, van den Hoogen FHJ, van de Putte LBA, van Venrooig WJ. 1998. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis‐specific autoantibodies. J Clin Invest 101:273–281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Ballori SP, Kushner I. Textbook of rheumatology, Vol. 1, 4th ed 40. Philadelphia: W.B. Saunders; 1993, Chap; p 671–679. [Google Scholar]
  • 54. Arvidsson NG, Gudbjornsson B, Hallgren R, Larsson A. 1998. Concordant message of different inflammatory markers in patients with rheumatoid arthritis. Upsala J Med Sci 103(1):35–42. [DOI] [PubMed] [Google Scholar]
  • 55. Kumon Y, Loose LD, Birbara CA, Sipe JD. 1997. Rheumatoid arthritis exhibits reduced acute phase and enhanced constitutive serum amyloid A protein in synovial fluid relative to serum. A comparison with C‐reactive protein. J Rheumatol 24:14–19. [PubMed] [Google Scholar]
  • 56. Doherty NS, Littman BH, Reilly K, Swindell AC, Buss JM, Anderson NL. 1998. Analysis of changes in acute‐phase plasma proteins in an acute inflammatory response and in rheumatoid arthritis using two‐dimensional gel electrophoresis. Electrophoresis 19:355–363. [DOI] [PubMed] [Google Scholar]
  • 57. Otterness IG. 1994. The value of C‐reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum 24:91–104. [DOI] [PubMed] [Google Scholar]
  • 58. Ballou SP, Kushner I. 1992. C‐reactive protein and the acute phase response. Adv Int Med 37:313–336. [PubMed] [Google Scholar]
  • 59. Tillet WS, Francis T. 1970. Serological reactions in pneumonia with a non‐protein somatic fraction of pneumococcus. J Exp Med 52:261–571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Sukenik S, Henkin J, Zimlichman S, et al. 1988. Serum and synovial fluid levels of serum amyloid A protein and C‐reactive protein in inflammatory and noninflammatory arthritis. J Rheumatol 15:942. [PubMed] [Google Scholar]
  • 61. Migata K, Kawabe Y, Tominaga M, Origuchi T, Aoyagi T, Eguchi K. 1998. Serum amyloid A protein induces production of matrix metalloproteinases by human synovial fibroblasts. Lab Invest 78(5):535–539. [PubMed] [Google Scholar]
  • 62. van Leeuwen MA, Westra J, Limburg PC, van Riel PLCM, van Rijswijk MH. 1995. Interleukin‐6 in relation to other proinflammatory cytokines, chemotactic activity and neutrophil activation in rheumatoid synovial fluid. Ann Rheum Dis 54:33–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. North J, Situnayake RD, Tikly M, et al. 1994. Interleukin 1 β, hand and foot bone mineral content, and the development of joint erosions in rheumatoid arthritis. Ann Rheum Dis 53:543–546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Luqmani R, Sheeran T, Robinson M, Richardson K, Winkles J, Emery P. 1994. Systemic cytokine measurements: their role in monitoring the response to therapy in patients with rheumatoid arthritis. Clin Exp Rheumatol 12:503–508. [PubMed] [Google Scholar]
  • 65. Shingu M, Fujikawa Y, Wada T, Nonaka S, Nobunaga M. 1995. Increased IL‐1 receptor antagonist (IL‐1ra) production and decreased IL‐iβ/1L‐1ra ratio in mononuclear cells from rheumatoid patients. Br J Rheumatol 34:24–30. [DOI] [PubMed] [Google Scholar]
  • 66. Hassfeld W, Steiner G, Smolen J. 1990. Anti‐RA 33. A valuable serologic marker for early diagnosis of rheumatoid arthritis. Clin Rheumatol 9:575. [Google Scholar]
  • 67. Hassfeld W, Steiner G, Hartmuth K, et al. 1989. Demonstration of a new antinuclear antibody (anti‐RA 33) that is highly specific for rheumatoid arthritis. Arthritis Rheum 32:1515–1520. [DOI] [PubMed] [Google Scholar]
  • 68. Steiner G, Hartmuth K, Skriner K, et al. 1992. Purification and partial sequencing of the nuclear autoantigen RA33 shows that it is indistinguishable from the A2 protein of the heterogeneous nuclear ribonucleoprotein complex. J Clin Invest 90:1061–1066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Skriner K, Steiner G, Sommergruber WH, Sinski A, Smolen JS. 1994. Anti‐RA33 autoantibodies may recognize epitopes in the N‐terminal region of hnRNP‐A2 (RA33). Clin Exp Rheumatol 12(Suppl 11):S79–S82. [PubMed] [Google Scholar]
  • 70. Meyer O, Tauxe F, Fabregas D, et al. 1993. Anti‐RA 33 antinuclear autoantibody in rheumatoid arthritis and mixed connective tissue disease: comparison with antikeratin and antiperinuclear antibodies. Clin Exp Rheumatol 11:473–478. [PubMed] [Google Scholar]
  • 71. Isenberg DA, Steiner G, Smolen JS. 1994. Clinical utility and serological connections of anti‐RA33 antibodies in systemic lupus erythematosus. J Rheumatol 21:1260–1263. [PubMed] [Google Scholar]
  • 72. Emlen W, Niebur J, Flanders G, Rutledge J. 1996. Measurement of serum hyaluronic acid in patients with rheumatoid arthritis: correlation with disease activity. J Rheumatol 23:974–978. [PubMed] [Google Scholar]
  • 73. Laurent TC, Laurent UB, Fraser JR. 1996. Serum hyaluronan as a disease marker. Ann Med 28:241–253. [DOI] [PubMed] [Google Scholar]
  • 74. Mansson B, Carey D, Alini M. 1995. Cartilage and bone metabolism in RA. Differences between rapid and slow progression of disease identified by serum markers of cartilage metabolism. J Clin Invest 95:1071–1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Saxne T, Geborek P, Mansson B, Heinegard D. 1995. Transactions of the 41st Annual Meeting, Orthopedic Research Society, Orlando, FL, 1995. p 34. [Google Scholar]
  • 76. Johansen JS, Jensen HS, Price PA. 1993. A new biochemical marker for joint injury. Analysis of YKL‐40 in serum and synovial fluid. Br J Rheumatol 32:949–955. [DOI] [PubMed] [Google Scholar]
  • 77. Saxne T, Zunino D, Heinegard D. 1995. Increased release of bone sialoprotein into synovial fluid reflects tissue destruction in rheumatoid arthritis. Arthritis Rheum 38:82–90. [DOI] [PubMed] [Google Scholar]
  • 78. Kollerup G, Hanwsen M, Herslev‐Petersen K. 1994. Urinary hydroxpyridinium cross‐links of collagen in rheumatoid arthritis, relation to disease activity and effects of methylprednisolone. Br J Rheumatol 33:816–820. [DOI] [PubMed] [Google Scholar]
  • 79. Hakala M, Risteli L, Manelius J, Nieminen P, Risteli J. 1993. Increased type I collagen degradation correlates with disease severity in rheumatoid arthritis. Ann Rheum Dis 52:866–869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Paimela L, Leinsalo‐Repo M, Risteli L, Hakala M, Helve T, Risteli J. 1994. Type I collagen degradation product in serum of patients with early rheumatoid arthritis: relationship to disease activity and radiological progression in a 3‐year follow‐up. Br J Rheumatol 33:1012–1016. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Laboratory Analysis are provided here courtesy of Wiley

RESOURCES