With respect to RA, I predict less reliance on the misnamed rheumatoid factor test, better recognition that RA is also probably a spectrum of related diseases (not just seropositive and seronegative RA) and that, likewise, better serological and genetic testing will help define patient subsets. I strongly believe that different subsets of “RA” patients will have antibodies to different citrullinated proteins and that we will end up having a RA-citrullinated panel of tests. Hopefully, this subsetting with coupling of better therapies, probably guided by genomics, will improve treatment.
Progress in rheumatology serology has been slow through the 1940s (RF and LE cell prep), 1950s (ANA and anti-DNA), 1960s (Sm, RNP, Ro, La) and 1990s (CCP). However, the understanding of the genetics of the disorders discussed here—as well as the therapies for them—has been accelerating. Let us hope that the future will bring new and better discoveries.
Peter H. Schur, MD, is professor of medicine at Harvard Medical School and the division of rheumatology, immunology and allergy in the Department of Medicine at Brigham and Women’s Hospital in Boston.
Acknowledgment: I am indebted to the work of many authors of UpToDate in Medicine, whose work provided a useful framework for the development of this paper as well as to Drs. Robert Shmerling, David Lee and Donald Bloch with whom I have written papers/chapters on this same subject.
References
- Bloch D. Measurement and clinical significance of antinuclear antibodies. UpToDate. 2014.
- American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Guidelines for immunologic laboratory testing in the rheumatic diseases: An introduction. Arthritis Rheum. 2002;47:429–433.
- Solomon DH, Kavanaugh AJ, Schur PH, et al. Evidence-based guidelines for the use of immunologic tests: Antinuclear Antibody testing. Arthritis Rheum. 2002;47:434–444.
- Sinclair D, Saas M, Williams D, et al. Can an ELISA replace immunofluorescence for the detection of anti-nuclear antibodies?—The routine use of anti-nuclear antibody screening ELISAs. Clin Lab. 2007;53:183–191.
- Avaniss-Aghajani E, Berzon S, Sarkissian A. Clinical value of multiplexed bead-based immunoassays for detection of autoantibodies to nuclear antigens. Clin Vaccine Immunol. 2007;14:505–509.
- Copple SS, Martins TB, Masterson C, et al. Comparison of three multiplex immunoassays for detection of antibodies to extractable nuclear antibodies using clinically defined sera. Ann N Y Acad Sci. 2007;1109:464–472.
- Caramaschi P, Ruzzenente O, Pieropan S, et al. Determination of ANA specificity using multiplexed fluorescent microsphere immunoassay in patients with ANA positivity at high titres after infliximab treatment: Preliminary results. Rheumatol Int. 2007;27:649–654.
- Biagini RE, Parks CG, Smith JP, et al. Analytical performance of the AtheNA MultiLyte ANA II assay in sera from lupus patients with multiple positive ANAs. Anal Bioanal Chem. 2007;388:613–618.
- Gonzalez C, Garcia-Berrocal B, Perez M, et al. Laboratory screening of connective tissue diseases by a new automated ENA screening assay (EliA Symphony) in clinically defined patients. Clin Chim Acta. 2005;359:109–114.
- Eissfeller P, Sticherling M, Scholz D, et al. Comparison of different test systems for simultaneous autoantibody detection in connective tissue diseases. Ann N Y Acad Sci. 2005;1050:327–339.
- Smith J, Onley D, Garey C, et al. Determination of ANA specificity using the UltraPlex platform. Ann N Y Acad Sci. 2005;1050:286–294.
- Martins TB, Burlingame R, von Muhlen CA, et al. Evaluation of multiplexed fluorescent microsphere immunoassay for detection of autoantibodies to nuclear antigens. Clin Diagn Lab Immunol. 2004;11:1054–1059.
- Bernardini S, Infantino M, Bellincampi L, et al. Screening of antinuclear antibodies: Comparison between enzyme immunoassay based on nuclear homogenates, purified or recombinant antigens and immunofluorescence assay. Clin Chem Lab Med. 2004;42:1155–1160.
- Nossent H, Rekvig OP. Antinuclear antibody screening in this new millennium: Farewell to the microscope? Scand J Rheumatol. 2001;30:123–126; discussion 127–128.
- Lopez-Hoyos M, Rodriguez-Valverde V, Martinez-Taboada V. Performance of antinuclear antibody connective tissue disease screen. Ann N Y Acad Sci. 2007;1109:322–329.
- Ghillani P, Rouquette AM, Desgruelles C, et al. Evaluation of the LIAISON ANA screen assay for antinuclear antibody testing in autoimmune diseases. Ann N Y Acad Sci. 2007;1109:407–413.
- Bonilla E, Francis L, Allam F, et al. Immunofluorescence microscopy is superior to fluorescent beads for detection of antinuclear antibody reactivity in systemic lupus erythematosus patients. Clin Immunol. 2007;124:18–21.
- Nifli AP, Notas G, Mamoulaki M, et al. Comparison of a multiplex, bead-based fluorescent assay and immunofluorescence methods for the detection of ANA and ANCA autoantibodies in human serum. J Immunol Methods. 2006;311:189–197.
- Shovman O, Gilburd B, Zandman-Goddard G, et al. Multiplexed AtheNA multi-lyte immunoassay for ANA screening in autoimmune diseases. Autoimmunity. 2005;38:105–109.
- Ulvestad E. Performance characteristics and clinical utility of a hybrid ELISA for detection of ANA. Apmis. 2001;109:217–222.
- Olaussen E, Rekvig OP. Screening tests for antinuclear antibodies (ANA): Selective use of central nuclear antigens as a rational basis for screening by ELISA. J Autoimmun. 1999;13:95–102.
- Homburger HA, Cahen YD, Griffiths J, Jacob GL. Detection of antinuclear antibodies: Comparative evaluation of enzyme immunoassay and indirect immunofluorescence methods. Arch Pathol Lab Med. 1998;122:993–999.
- Gniewek RA, Stites DP, McHugh TM, et al. Comparison of antinuclear antibody testing methods: Immunofluorescence assay versus enzyme immunoassay. Clin Diagn Lab Immunol. 1997;4:185–188.
- Bloch D. Antibodies to DNA, SM, and RNP. UpToDate. 2014.
- Hahn BH. Antibodies to DNA. New Engl J Med. 1998;338:1359.
- Kavanaugh AF, Solomon DH, the American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Guidelines for immunologic laboratory testing in the rheumatic diseases: Anti-DNA antibody tests. Arthritis Rheum. 2002; 47:546–555.
- Benito-Garcia E, Schur PH, Lahita R. Guidelines for Immunologic laboratory testing in the rheumatic diseases: Anti-Sm and Anti-RNP antibody tests. Arthritis Rheum. 2004; 51:1030–1044.
- Reichlin M. Clinical significance of anti-Ro/SSA and anti-La/SSB antibodies. UpToDate. October 2008.
- Reveille JD, Sherrer YRS, Solomon DH, et al. Evidenced-based guidelines for the use of immunological laboratory tests: Anti-Ro (SS-A) and La (SS-B): A report from the ACR Ad Hoc Committee on Immunological Testing Guidelines. Submitted for publication.
- Bloch D. Antiribosomal P protein antibodies. UpToDate. 2014.
- Denton CP. Classification of scleroderma. UpToDate. 2014.
- Shmerling RH. Origin and utility of measurement of rheumatoid factors. UpToDate. 2014.
- Shmerling RH, Delbanco TL. The rheumatoid factor: An analysis of clinical utility. Am J Med. 1991;91:528.
- Kavanaugh AF, Solomon DH, the American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Guidelines for immunologic laboratory testing in the rheumatic diseases. Anti-DNA antibody tests. Arthritis Rheum. 2002;47:546–555.
- Schellekens GA, de Jong BA, van den Hoogen FH, et al. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998;101:273–281.
- Girbal-Neuhauser E, Durieux JJ, Arnaud M, et al. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol. 1999;162:585–594.
- Lee DM, Phillips R, Hagan EM, et al. Quantifying anti-cyclic citrullinated peptide titres: Clinical utility and association with tobacco exposure in patients with rheumatoid arthritis. Ann Rheum Dis. 2009;68:201–208.
- 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;146:797–808.
- van der Helm-van Mil AH, Verpoort KN, Breedveld FC, et al. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther. 2005;7:R949–R958.
- van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE. The devil in the details: The emerging role of anticitrulline autoimmunity in rheumatoid arthritis. J Immunol. 2005;175:5575–5580.
- Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741–2749.
- Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50:380–386.
- van Gaalen FA, van Aken J, Huizinga TW, et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum. 2004;50:2113–2121.
- Berglin E, Padyukov L, Sundin U, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther. 2004;6(4):R303–R308.
- Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54:38–46.
- Lee HS, Irigoyen P, Kern M, et al. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: A mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum. 2007;56:1745–1753.
- Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. Cutting edge: The conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol. 2003;171:538–541.
- Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum. 1996;39:732–735.
- Heliovaara M, Aho K, Aromaa A, Knekt P, Reunanen A. Smoking and risk of rheumatoid arthritis. J Rheumatol. 1993;20:1830–1835.
- Uhlig T, Hagen KB, Kvien TK. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J Rheumatol. 1999;26:47–54.
- Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: Results from a population based case-control study, using incident cases. Ann Rheum Dis.;62:835–841.
- Makrygiannakis D, af Klint E, Lundberg IE, et al. Citrullination is an inflammation-dependent process. Ann Rheum Dis. 2006;65:1219–1222.
- Vossenaar ER, Nijenhuis S, Helsen MM, et al. Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum. 2003;48:2489–2500.
- Kuhn KA, Kulik L, Tomooka B, et al. Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest. 2006;116:961–973.
- Lundberg K, Nijenhuis S, Vossenaar ER, et al. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res Ther. 2005;7(3):R458–R467.
- Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, et al. The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol. 2001;166:4177–4184.
- Liao KP, Batra KL, Chibnik L, Schur PH, Costenbader KH. Anti-CCP revised criteria for the Classification of Rheumatoid Arthritis. Ann Rheum Dis. 2008;67:1557–1561.
- Yaniv G Twig G, Shor D B-A, et al. A volcanic explosion of autoantibodies in systemic lupus eryhthematosus: A diversity of 180 different antibodies found in SLE patients. Autoimmunity Reviews. 2014; In press.
- Schur PH, Sandson J. Immunologic factors and clinical activity in systemic lupus erythematosus. N Engl J Med. 1968 Mar 7;278(10):533–538.
- Provost TT, Razzaque A, Maddison PJ, Reichlin M. Antibodies to cytoplasmic antigens in lupus erythematosus. Serologic markers for systemic disease. Arthritis Rheum. 1977 Nov-Dec;20(8):1457–1463.
- Alspaugh MA, Tan EM. Antibodies to cellular antigens in Sjögren’s syndrome. J Clin Invest. 1975 May;55(5):1067–1073.
- Aletha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569–2581.