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Seronegative Rheumatoid Arthritis: Fact or Fiction?

Seronegative Rheumatoid Arthritis: Fact or Fiction? Abstract • Patients with clinical features of rheumatoid arthritis (RA) but negative rheumatoid factor (RF) present a diagnostic challenge. The seronegative spondyloarthropathy (SNSA) syndromes, previously believed to be "rheumatoid arthritis variants," eg, Reiter's syndrome and psoriatic arthritis, are now considered to be genetically separate from RA and have been shown to be closely associated with HLA-B27. This syndromic discrimination has raised question as to the validity of RF negative RA (ie, seronegative RA). Demographic, clinical, and roentgenologic features of seronegative RA and SNSA are compared. Also, more common diagnoses that may simulate seronegative RA are outlined according to onset age of arthritis. Recent concepts of RF positivity and HLA-DR4 correlations are reviewed. Multiple unknown factors contribute to the currently recognized syndrome of RA. Its diagnosis continues to rest on an aggregate of host, clinical, immunologic, and radiologic features. (Arch Intern Med 1983;143:2167-2172) References 1. Masi AT, Medsger TA: Epidemiology of the rheumatic diseases , in McCarty DJ (ed): Arthritis and Allied Conditions , ed 9. Philadelphia, Lea & Febiger, 1979, pp 11-35. 2. MikkelsenWM, Dodge HJ, Duff IF, et al: Estimate of the prevalence of rheumatic diseases in the population of Tecumseh, Michigan, 1959-1960. J Chronic Dis 1967;20:351-369.Crossref 3. Singer JM: Standardization of the latex test for rheumatoid arthritis serology. Bull Rheum Dis 1974;24:762-769. 4. Valkenburg HA, Ball J, Burch TA, et al: Rheumatoid factors in a rural population. Ann Rheum Dis 1966;25:497-508. 5. Kunkel HG, Simon HJ, Fudenberg H: Observations concerning positive serologie reactions in certain patients with sarcoidosis and other hyperglobulinemic states. Arthritis Rheum 1958;1:289-296.Crossref 6. Carson DA, Bayer AS, Eisenberg RA, et al: IgG rheumatoid factor in SBE: Relationship to IgM rheumatoid factor and circulating immune complexes. Clin Exp Immunol 1978;31:100-103. 7. Masi AT, Maldonado-Cocco JA, Kaplan SB, et al: Prospective study of the early course of rheumatoid arthritis in young adults: Comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome. Semin Arthritis Rheum 1976;5:299-326.Crossref 8. Moore TL, Dorner RW, Weiss TD, et al: 19S IgM hidden rheumatoid factor in juvenile rheumatoid arthritis. Pediatr Res 1980;14:1135-1138.Crossref 9. Bluestone R, Goldberg L, Cracchiolo A: Hidden rheumatoid factor in seronegative nodular rheumatoid arthritis. Lancet 1969;2:878-879.Crossref 10. Alarcon GS, Koopman WJ, Schrohenloher RE: In vitro synthesis of IgM and IgM rheumatoid factor in seronegative arthritides. Arthritis Rheum 1982;25( (suppl) ):S121.Crossref 11. Slaughter L, Carson DA, Jensen FC: In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med 1978;148:1429-1434.Crossref 12. Koopman WJ, Schrohenloher RE: Enhanced in vitro synthesis of IgM rheumatoid factor in rheumatoid arthritis. Arthritis Rheum 1980;23:985-992.Crossref 13. Brewerton DA: HLA-B27 and the inheritance of susceptibility to rheumatic diseases. Arthritis Rheum 1976;19:656-668.Crossref 14. Calin A, Marks SH: The case against seronegative rheumatoid arthritis. Am J Med 1981;70:992-994.Crossref 15. Esdaile JM, Dwosh IL, Urowitz MB, et al: HLA B27 in rheumatoid factor-negative polyarthritis. Ann Intern Med 1977;86:699-702.Crossref 16. Dequecker J, Decock T, Walravens M, et al: A systematic survey of the HLA B27 prevalence in inflammatory rheumatic diseases. J Rheumatol 1978;5:452-459. 17. Stastny P: Joint report: Rheumatoid arthritis , in Terasaki PI (ed): Histocompatibility Typing-1980 . Los Angeles, UCLA Tissue Typing Laboratory, 1980, pp 681-686. 18. Sakurami T, Ueno Y, Okumura H, et al: HLA-DR specificities among Japanese with rheumatoid arthritis. Arthritis Rheum 1981;24:866.Crossref 19. Karr RW, Rodey GE, Lee T, et al: Association of HLA-DRw4 with rheumatoid arthritis in black and white patients. Arthritis Rheum 1980;23: 1241-1245.Crossref 20. Alarcon GS, Koopman WJ, Acton RT, et al: DR antigen distribution in blacks with rheumatoid arthritis. J Rheumatol 1983;10:579-583. 21. Arnett FC, McClusky OE, Schacter BZ, et al: Incomplete Reiter's syndrome: Discriminating features and HL-A W27 in diagnosis. Ann Intern Med 1976;84:8-12.Crossref 22. Joliat G, Ferro A, Jeannet M, et al: HLA-B27 antigen in diagnosis of atypical seronegative inflammatory arthropathy. Ann Rheum Dis 1976;35: 531-533.Crossref 23. Fallahi S, Halla JT, Hardin JG Jr: The influence of B27 antigen on the clinical and radiographie picture of definite or classical rheumatoid arthritis. J Rheumatol 1982;9:13-17. 24. Alarcon GS, Koopman WJ, Acton RT, et al: Seronegative rheumatoid arthritis: A distinct immunogenetic disease? Arthritis Rheum 1982;25:502-507.Crossref 25. Calin A: HLA-B27: To type or not to type? Ann Intern Med 1980;92:208-211.Crossref 26. Khan MA, Khan MK: Diagnostic value of HLA-B27 testing in ankylosing spondylitis and Reiter's syndrome. Ann Intern Med 1982;96: 70-76.Crossref 27. Terkeltaub R, Esdaile J, Decary F, et al: A clinical study of older age onset rheumatoid arthritis with comparison to a younger onset group. J Rheumatol 1983;10:418-424. 28. O'Duffy JD, Wahner HW, Hunder GG: Joint imaging in polymyalgia rheumatica. Mayo Clin Proc 1976;51:519-524. 29. Yunus M, Plattner PF, Masi AT, et al: Ulnar deviation of the fingers in gout simulating rheumatoid arthritis. J Rheumatol 1982;9:619-623. 30. Ropes MW, Bennett GA, Cobb S, et al: 1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 1959;9:175-176. 31. Cathcart ES, O'Sullivan JB: Rheumatoid arthritis in a New England town: A prevalence study in Sudbury, Massachusetts. N Engl J Med 1970; 282:421-424.Crossref 32. Feigenbaum SF, Masi AT, Schoon CM: Classification studies of rheumatoid factor negative (seronegative) peripheral arthritis. Arthritis Rheum 1981;24( (suppl 4) ):S99.Crossref 33. Lawrence JS, Bennett PH: Benign polyarthritis. Ann Rheum Dis 1960;19:20-30.Crossref 34. Yunus M, Masi AT, Calabro JJ, et al: Primary fibromyalgia (fibrositis): Clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 1981;11:151-171.Crossref 35. Feigenbaum SL, Masi AT, Kaplan SB: Prognosis in rheumatoid arthritis: Longitudinal study of newly diagnosed younger adult patients. Am J Med 1979;66:377-384.Crossref 36. Dixon ASJ: 'Rheumatoid arthritis' with negative serological reaction. Ann Rheum Dis 1960;19:209-228.Crossref 37. Lawrence JS: Rheumatoid arthritis: Nature or nurture? Ann Rheum Dis 1970;29:357-379.Crossref 38. Engelman EG, Sponzilli EE, Batey ME, et al: Mixed lymphocyte reaction in healthy women with rheumatoid factor: Lack of association with HLA-Dw4. Arthritis Rheum 1978;21:690-693.Crossref 39. Alarcon GS, Koopman WJ, Schrohenloher RE: Differential patterns of in vitro IgM rheumatoid factor synthesis in seronegative and seropositive rheumatoid arthritis. Arthritis Rheum 1982;25:150-155.Crossref 40. Murray C, Mann DL, Gerber LN, et al: Histocompatibility alloantigens in psoriasis and psoriatic arthritis: Evidence for the influence of multiple genes in the major histocompatibility complex. J Clin Invest 1980;66:670-675.Crossref 41. Trentham DE, Kammer GM, McCune WJ, et al: Autoimmunity to collagen: A shared feature of psoriatic and rheumatoid arthritis. Arthritis Rheum 1981;24:1363-1369.Crossref 42. Khan MA, Kushner I, Ballon S, et al: Familial rheumatoid arthritis and HLA-DRw4. Lancet 1979;1:921-922.Crossref 43. Khan MA, Kushner I, Weitkamp LR: Genetics of HLA-associated disease: Rheumatoid arthritis. Tissue Antigens , in press. 44. Rosen RD, Brewer EJ, Sharp EM, et al: Familial rheumatoid arthritis: Linkage of HLA to disease susceptibility locus in four families where proband presented with juvenile rheumatoid arthritis. J Clin Invest 1980;65:629-642.Crossref 45. Lally EV, Baker DG, Horwitz HM: Seronegative peripheral arthritis in B27 positive monozygotic twin sisters. Arthritis Rheum 1982;25:1490-1493.Crossref 46. Mitchell DM, Fries JF: An analysis of the American Rheumatism Association criteria for rheumatoid arthritis. Arthritis Rheum 1982;25:481-487.Crossref 47. Lulls P, Cappellacci S, Morellini M, et al: HLA antigens and rheumatoid arthritis. Arthritis Rheum 1983;26:1053-1054.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Seronegative Rheumatoid Arthritis: Fact or Fiction?

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Publisher
American Medical Association
Copyright
Copyright © 1983 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.1983.00350110157031
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Abstract

Abstract • Patients with clinical features of rheumatoid arthritis (RA) but negative rheumatoid factor (RF) present a diagnostic challenge. The seronegative spondyloarthropathy (SNSA) syndromes, previously believed to be "rheumatoid arthritis variants," eg, Reiter's syndrome and psoriatic arthritis, are now considered to be genetically separate from RA and have been shown to be closely associated with HLA-B27. This syndromic discrimination has raised question as to the validity of RF negative RA (ie, seronegative RA). Demographic, clinical, and roentgenologic features of seronegative RA and SNSA are compared. Also, more common diagnoses that may simulate seronegative RA are outlined according to onset age of arthritis. Recent concepts of RF positivity and HLA-DR4 correlations are reviewed. Multiple unknown factors contribute to the currently recognized syndrome of RA. Its diagnosis continues to rest on an aggregate of host, clinical, immunologic, and radiologic features. (Arch Intern Med 1983;143:2167-2172) References 1. Masi AT, Medsger TA: Epidemiology of the rheumatic diseases , in McCarty DJ (ed): Arthritis and Allied Conditions , ed 9. Philadelphia, Lea & Febiger, 1979, pp 11-35. 2. MikkelsenWM, Dodge HJ, Duff IF, et al: Estimate of the prevalence of rheumatic diseases in the population of Tecumseh, Michigan, 1959-1960. J Chronic Dis 1967;20:351-369.Crossref 3. Singer JM: Standardization of the latex test for rheumatoid arthritis serology. Bull Rheum Dis 1974;24:762-769. 4. Valkenburg HA, Ball J, Burch TA, et al: Rheumatoid factors in a rural population. Ann Rheum Dis 1966;25:497-508. 5. Kunkel HG, Simon HJ, Fudenberg H: Observations concerning positive serologie reactions in certain patients with sarcoidosis and other hyperglobulinemic states. Arthritis Rheum 1958;1:289-296.Crossref 6. Carson DA, Bayer AS, Eisenberg RA, et al: IgG rheumatoid factor in SBE: Relationship to IgM rheumatoid factor and circulating immune complexes. Clin Exp Immunol 1978;31:100-103. 7. Masi AT, Maldonado-Cocco JA, Kaplan SB, et al: Prospective study of the early course of rheumatoid arthritis in young adults: Comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome. Semin Arthritis Rheum 1976;5:299-326.Crossref 8. Moore TL, Dorner RW, Weiss TD, et al: 19S IgM hidden rheumatoid factor in juvenile rheumatoid arthritis. Pediatr Res 1980;14:1135-1138.Crossref 9. Bluestone R, Goldberg L, Cracchiolo A: Hidden rheumatoid factor in seronegative nodular rheumatoid arthritis. Lancet 1969;2:878-879.Crossref 10. Alarcon GS, Koopman WJ, Schrohenloher RE: In vitro synthesis of IgM and IgM rheumatoid factor in seronegative arthritides. Arthritis Rheum 1982;25( (suppl) ):S121.Crossref 11. Slaughter L, Carson DA, Jensen FC: In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med 1978;148:1429-1434.Crossref 12. Koopman WJ, Schrohenloher RE: Enhanced in vitro synthesis of IgM rheumatoid factor in rheumatoid arthritis. Arthritis Rheum 1980;23:985-992.Crossref 13. Brewerton DA: HLA-B27 and the inheritance of susceptibility to rheumatic diseases. Arthritis Rheum 1976;19:656-668.Crossref 14. Calin A, Marks SH: The case against seronegative rheumatoid arthritis. Am J Med 1981;70:992-994.Crossref 15. Esdaile JM, Dwosh IL, Urowitz MB, et al: HLA B27 in rheumatoid factor-negative polyarthritis. Ann Intern Med 1977;86:699-702.Crossref 16. Dequecker J, Decock T, Walravens M, et al: A systematic survey of the HLA B27 prevalence in inflammatory rheumatic diseases. J Rheumatol 1978;5:452-459. 17. Stastny P: Joint report: Rheumatoid arthritis , in Terasaki PI (ed): Histocompatibility Typing-1980 . Los Angeles, UCLA Tissue Typing Laboratory, 1980, pp 681-686. 18. Sakurami T, Ueno Y, Okumura H, et al: HLA-DR specificities among Japanese with rheumatoid arthritis. Arthritis Rheum 1981;24:866.Crossref 19. Karr RW, Rodey GE, Lee T, et al: Association of HLA-DRw4 with rheumatoid arthritis in black and white patients. Arthritis Rheum 1980;23: 1241-1245.Crossref 20. Alarcon GS, Koopman WJ, Acton RT, et al: DR antigen distribution in blacks with rheumatoid arthritis. J Rheumatol 1983;10:579-583. 21. Arnett FC, McClusky OE, Schacter BZ, et al: Incomplete Reiter's syndrome: Discriminating features and HL-A W27 in diagnosis. Ann Intern Med 1976;84:8-12.Crossref 22. Joliat G, Ferro A, Jeannet M, et al: HLA-B27 antigen in diagnosis of atypical seronegative inflammatory arthropathy. Ann Rheum Dis 1976;35: 531-533.Crossref 23. Fallahi S, Halla JT, Hardin JG Jr: The influence of B27 antigen on the clinical and radiographie picture of definite or classical rheumatoid arthritis. J Rheumatol 1982;9:13-17. 24. Alarcon GS, Koopman WJ, Acton RT, et al: Seronegative rheumatoid arthritis: A distinct immunogenetic disease? Arthritis Rheum 1982;25:502-507.Crossref 25. Calin A: HLA-B27: To type or not to type? Ann Intern Med 1980;92:208-211.Crossref 26. Khan MA, Khan MK: Diagnostic value of HLA-B27 testing in ankylosing spondylitis and Reiter's syndrome. Ann Intern Med 1982;96: 70-76.Crossref 27. Terkeltaub R, Esdaile J, Decary F, et al: A clinical study of older age onset rheumatoid arthritis with comparison to a younger onset group. J Rheumatol 1983;10:418-424. 28. O'Duffy JD, Wahner HW, Hunder GG: Joint imaging in polymyalgia rheumatica. Mayo Clin Proc 1976;51:519-524. 29. Yunus M, Plattner PF, Masi AT, et al: Ulnar deviation of the fingers in gout simulating rheumatoid arthritis. J Rheumatol 1982;9:619-623. 30. Ropes MW, Bennett GA, Cobb S, et al: 1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 1959;9:175-176. 31. Cathcart ES, O'Sullivan JB: Rheumatoid arthritis in a New England town: A prevalence study in Sudbury, Massachusetts. N Engl J Med 1970; 282:421-424.Crossref 32. Feigenbaum SF, Masi AT, Schoon CM: Classification studies of rheumatoid factor negative (seronegative) peripheral arthritis. Arthritis Rheum 1981;24( (suppl 4) ):S99.Crossref 33. Lawrence JS, Bennett PH: Benign polyarthritis. Ann Rheum Dis 1960;19:20-30.Crossref 34. Yunus M, Masi AT, Calabro JJ, et al: Primary fibromyalgia (fibrositis): Clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 1981;11:151-171.Crossref 35. Feigenbaum SL, Masi AT, Kaplan SB: Prognosis in rheumatoid arthritis: Longitudinal study of newly diagnosed younger adult patients. Am J Med 1979;66:377-384.Crossref 36. Dixon ASJ: 'Rheumatoid arthritis' with negative serological reaction. Ann Rheum Dis 1960;19:209-228.Crossref 37. Lawrence JS: Rheumatoid arthritis: Nature or nurture? Ann Rheum Dis 1970;29:357-379.Crossref 38. Engelman EG, Sponzilli EE, Batey ME, et al: Mixed lymphocyte reaction in healthy women with rheumatoid factor: Lack of association with HLA-Dw4. Arthritis Rheum 1978;21:690-693.Crossref 39. Alarcon GS, Koopman WJ, Schrohenloher RE: Differential patterns of in vitro IgM rheumatoid factor synthesis in seronegative and seropositive rheumatoid arthritis. Arthritis Rheum 1982;25:150-155.Crossref 40. Murray C, Mann DL, Gerber LN, et al: Histocompatibility alloantigens in psoriasis and psoriatic arthritis: Evidence for the influence of multiple genes in the major histocompatibility complex. J Clin Invest 1980;66:670-675.Crossref 41. Trentham DE, Kammer GM, McCune WJ, et al: Autoimmunity to collagen: A shared feature of psoriatic and rheumatoid arthritis. Arthritis Rheum 1981;24:1363-1369.Crossref 42. Khan MA, Kushner I, Ballon S, et al: Familial rheumatoid arthritis and HLA-DRw4. Lancet 1979;1:921-922.Crossref 43. Khan MA, Kushner I, Weitkamp LR: Genetics of HLA-associated disease: Rheumatoid arthritis. Tissue Antigens , in press. 44. Rosen RD, Brewer EJ, Sharp EM, et al: Familial rheumatoid arthritis: Linkage of HLA to disease susceptibility locus in four families where proband presented with juvenile rheumatoid arthritis. J Clin Invest 1980;65:629-642.Crossref 45. Lally EV, Baker DG, Horwitz HM: Seronegative peripheral arthritis in B27 positive monozygotic twin sisters. Arthritis Rheum 1982;25:1490-1493.Crossref 46. Mitchell DM, Fries JF: An analysis of the American Rheumatism Association criteria for rheumatoid arthritis. Arthritis Rheum 1982;25:481-487.Crossref 47. Lulls P, Cappellacci S, Morellini M, et al: HLA antigens and rheumatoid arthritis. Arthritis Rheum 1983;26:1053-1054.Crossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Nov 1, 1983

References