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Anti-neutrophil cytoplasm antibodies (ANCA) in rheumatoid arthritis: relationship to HLA-DR phenotypes, rheumatoid factor, anti-nuclear antibodies and disease severity

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Abstract

To investigate a possible relationship between the presence of anti-neutrophil cytoplasm antibodies (ANCA), rheumatoid factors (RF), anti-nuclear antibodies (ANA), disease severity and HLA-DR phenotypes, 46 consecutive ANCA+ and 48 ANCA-, clinically well-documented RA patients were studied for RF, ANA and HLA-DR phenotypes. The 46 ANCA+ patients showed predominantly an atypical perinuclear staining pattern (89%). ANCA positivity was associated with higher RF titres (P<0.005) and advanced functional Steinbrocker grades III/IV (P<0.015). ANCA+ patients were also more often positive for ANA than ANCA- patients (P<0.008). There was no correlation between ANCA positivity and certain HLA-DR phenotypes although the frequency of DR4+ (67% vs 52%) and, in particular, of DR4+ blanks (phenotypically homozygous) was increased in ANCA+ as compared to ANCA- patients (20% vs 8%). DR4-DR1- RA patients were twice as frequent in the ANCA- than in the ANCA+ group (22.9% vs 8.7%). Correspondingly, the DR4+DR1- phenotype was increased among ANCA+ RA patients. Regarding functional Steinbrocker grades, the DR4+ phenotypes were slightly but not significantly increased in grades III and IV whereas ANCA positivity was significantly associated with severe functional Steinbrocker grades III/IV (66% ANCA+ vs 39% ANCA-,P<0.015). ANCA positivity identified a population of RA patients with a long-standing and severe clinical course of the disease. There was no correlation between ANCA positivity and certain HLA-DR phenotypes.

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References

  1. Lüdemann J, Utecht B, Gross WL (1990) Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis recognize an elastinolytic enzyme. J Exp Med 171:357–362

    Google Scholar 

  2. Van der Woude FJ, Rasmussen N, Wiik A, Van Es LA, Van der Hem GK, Lobatto S, Permin H, Van der Giessen M (1985) Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet I 23:425–429

    Google Scholar 

  3. Nölle B, Specks U, Lüdemann J, Rohrbach MS, DeRemee RA, Gross WL (1989) Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener's granulomatosis. Ann Intern Med 111:28–40

    Google Scholar 

  4. Gross WL, Lüdemann J, Kiefer G, Lehmann H (1986) Anticytoplasmic antibodies in Wegener's granulomatosis. Lancet I:806

    Google Scholar 

  5. Falk RJ, Jennette JC (1988) Anti-neutrophil cytoplasmic autoantibodies with specificity for myelopoeroxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 318:1651–1657

    Google Scholar 

  6. Cohen Tervaert JW, Van der Woude FJ, Fauci AS, Ambrus JL, Velosa J, Keane WF, Meyer S, Van der Giessen M, The TH, Van der Hem GK Kallenberg CGM (1989) Association between active Wegener's granulomatosis and anti-cytoplasmic antibodies. Arch Intern Med 149:2461–2465

    Google Scholar 

  7. Cohen Tervaert JW, Goldschmeding R, Elema J, Limburg PC, Van der Giessen M, Huitema MG, Koolen MI, Hene RJ, The TH, Van der Hem GK, von dem Borne AEGKr, Kallenberg CGM (1990) Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum 33:1264–1272

    Google Scholar 

  8. Saxon A, Shanahan F, Landers C, Ganz T, Targan S (1990) A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease. J Allergy Clin Immunol 86:202–210

    Google Scholar 

  9. Rump JA, Schölmerich J, Gross V, Roth H, Helfesrider R, Rauthmann A, Lüdemann J, Gross WL, Peter HH (1990) A new type of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) in active ulcerative colitis but not in Crohn's disease. Immunobiology 181:407–413

    Google Scholar 

  10. Duerr RH, Targan SR, Landers CJ, LaRusso NF, Lindsay KL, Wiesner RH, Shanahan F (1991) Neutrophil cytoplasmic antibodies: a link between primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 100:1385–1391

    Google Scholar 

  11. Peter HH, Metzger D, Rump JA, Röther E (1993) ANCA in discases other than systemic vasculitis. Clin Exp Immunol 93 [Suppl]:12–14

    Google Scholar 

  12. Mulder AHL, Horst G, Haagsma E, Limburg P, Kleibeuker J, Kallenberg C (1993) Prevalence and charactezation of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology 17:411–417

    Google Scholar 

  13. Juby C, Johnston C, Davis P (1992) Antinuclear and antineutrophil cytoplasmic antibodies (ANCA) in the sera of patients with Felty's syndrome. Br J Rheumatol 31:185–188

    Google Scholar 

  14. Kemmett D, Harrison DJ, Hunter JA (1991) Antibodies to neutrophil cytoplasmic antigens: serologic marker for Sweet's syndrome. Am Acad Dermatol 24:967–969

    Google Scholar 

  15. Targan SR, Saxon A, Landers C, Gans C, Shanahan F (1989) Serum antineutrophil cytoplasmic autoantibodies distinguish ulcerative colitis from Crohn's disease pateints. Gastroenterology 96:A505

    Google Scholar 

  16. Wiik A (1980) Granulocyte specific antinuclear antibodies. Allergy 35:263–289

    Google Scholar 

  17. Faber V, Elling P (1966) Leukocyte-specific antinuclear factors in patients with Felty's syndrome, rheumatoid arthritis, systemic lupus erythermatosus and other diseases. Acta Med Scand 179:257–267

    Google Scholar 

  18. Savage CO, Winearls Jones S (1987) Prospective study of radioimmuno-assay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet I:1389–1393

    Google Scholar 

  19. Savige JA, Gallicchio MC, Stockman A, Cunningham J, Rowley MJ, Georgiou T, Davies D (1991) Anti-neutrophil cytoplasm antibodies in rheumatoid arthritis. Clin Exp Immunol 86:92–98

    Google Scholar 

  20. Metzger D, Röther E, Melchers I, Lang B, Peter HH (1993) Anti-Neutrophilen-Zytoplasma-Antikörper (ANCA) bei rheumatoider Arthritis: Spezifität und klinische Relevanz? Immun Infekt 21 [Suppl 1]:18–20

    Google Scholar 

  21. Mulder AHL, Horst G, Van Leeuwen MA, Limburg PC, Kallenberg CGM (1993) Antineutrophil cytoplasmic antibodies in rheumatoid arthritis. Arthritis Rheum 36:1054–1060

    Google Scholar 

  22. Halbwachs-Mecarelli L, Nusbaum P, Noel LH, Reumaux D, Erlinger S (1992) Antineutrophil cytoplasmic antibodies (ANCA) directed against cathepsin G in ulcerative colitis, Crohn's disease and primary sclerosing cholangitis. Clin Exp Immunol 90:79–84

    Google Scholar 

  23. Falk RJ, Charles LA, Jennette JC (1990) Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA 87:4115–4119

    Google Scholar 

  24. Coremans IEM, Hagen EC, Daha MR, Van der Woude FJ, Van der Voort EAM, Kleijburg-van der Keur C, Breedveld FC (1992) Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis. Arthritis Rheum 35: 1466–1475

    Google Scholar 

  25. Schmitt WH, Csernok E, Flesch BK, Hauschild S, Gross WL (1993) Autoantibodies directed against lysozyme. A new target antigen for anti-neutrophil cytoplasmic antibodies. In: Gross WL (ed) ANCA-associated vasculitides. Plenum, London 267–272

    Google Scholar 

  26. Wiik A, Jensen E, Friis J (1974) Granulocyte-specific antinuclear factors in synovial fluids and sera from patients with rheumatoid arthritis. Ann Rheum Dis 33:515–522

    Google Scholar 

  27. Wiik A (1994) Complement-fixing granulocyte-specific antinuclear factors in neutropenic cases of rheumatoid arthritis. Immunology 20:1127–1134

    Google Scholar 

  28. Goldschmeding R, Cohen Tervaert JW, Van der Schoot CE, Kallenberg CGM, von dem Borne AEGKr (1989) ANCA, antimyeloperoxidase and anti-elastase: three members of a novel class of autoantibodies against myeloid lysosomal enzyme. In: Proceedings of the First International Workshop on ANCA. APMIS, Copenhagen, pp 48–49

    Google Scholar 

  29. Martensson U, Nässberger L (1992) Circulating autoantibodies directed against betaglucuronidase. Autoimmunity 11:213–214

    Google Scholar 

  30. Lang B, Melchers I, Urlacher A, Tanzi-Fetta RF, Tongio MM, Peter HH (1990) HLA-DR1 and DRw6 association in DR4-negative rheumatoid arthritis patients. Rheumatol Int 10:171–175

    Google Scholar 

  31. Woodrow JC, Nichol FE, Zaphiropoulos G (1981) DR antigens and rheumatoid arthritis: a study of two populations. BMJ 283: 1287–1288

    Google Scholar 

  32. Becking A, Pluschke G, Krawinkel U, Melchers I, Peter HH, Lang B (1993) HLA-DRB1 gene sequences in HLA-DR4 positive and negative patients with rheumatoid arthritis. Eur J Immunogenetics 20:83–89

    Google Scholar 

  33. McCusker CT, Reid B, Green D, Gladman DD, Buchanan WW, Singal DP (1991) HLA-D region antigens in patients with rheumatoid arthritis. Arthritis Rheum 34:192–197

    Google Scholar 

  34. Husby G, Gran JT, Ostensen M, Johannessen A, Thorsby E (1979) HLA-DRw4 and rheumatoid arthritis. Lancet I:548–549

    Google Scholar 

  35. Jaraquemada D, Ollier W, Awad J, Young A, Silman A, Roitt IM, Corbett M, Hay F, Cosh JA, Maini RN (1986) HLA and rheumatoid arthritis: a combined analysis of 440 British patients. Ann Rheum Dis 45:627–636

    Google Scholar 

  36. Karr RW, Rodney GE, Lee T, Schwartz BD (1980) Association of HLA-DRw4 with rheumatoid arthritis in black and white patients. Arthritis Rheum 23:1241–1245

    Google Scholar 

  37. Lanchbury JS (1992) The HLA association with rheumatoid arthritis. Clin Exp Rheumatol 10:301–305

    Google Scholar 

  38. Ollier W, Carthy D, Cutbush S, Okoye R, Awad J, Fielder A, Silman A, Festenstein H (1989) HLA-DR4 associated Dw types in rheumatoid arthritis. Tissue Antigens 33:30–35

    Google Scholar 

  39. Legrand L, Lathrop GM, Marcelli-Barge A, Dryll A, Bardin T, Debeyre N, Poirier JC, Schmid M, Ryckewaert A, Dausset J (1984) HLA-DR genotype risks in seropositive rheumatoid arthritis. Am J Hum Genet 36:690–699

    Google Scholar 

  40. Brackertz D, Wernet P (1980) Genetic analysis of rheumatoid arthritis: population and family studies. Arthritis Rheum 23:656–660

    Google Scholar 

  41. Lee SH, Gregersen PK, Shen HH, Nunez-Roldan A, Silver J, Winchester RJ (1984) Strong association of rheumatoid arthritis with the presence of a polymorphic Ia epitope defined by a monoclonal antibody: comparison with the allodeterminant DR4. Rheumatol Int 4[Suppl]:17–23

    Google Scholar 

  42. Lang B, Kohlbrenner S, Melchers I, Urlacher A, Tanzi-Fetta RT, Tongio MM, Peter HH (1994) HLA-DR4 and severity in patients with rheumatoid arthritis. Eur J Immunogenetics (in press)

  43. Olsen NJ, Callahan LF, Brooks RH, Nance EP, Kaye JJ, Stastny P, Pincus T (1988) Associations of HLA-DR4 with rheumatoid factor and radiographic severity in rheumatoid arthritis. Am J Med 84:257–264

    Google Scholar 

  44. Roitt JM, Corbett M, Festenstein H, Jaraquemada D, Papasteriadis C, Hay FC, Nineham LJ (1978) HLA-DRw4 and prognosis in rheumatoid arthritis. Lancet I:990

    Google Scholar 

  45. Van Zeben D, Hazes JMW, Zwinderman EH, Cats A, Schreuder GMT, D'Amoro J, Breedveld FC (1991) Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Arthritis Rheum 34:822–825

    Google Scholar 

  46. Hüge H, Loreck D, Richter KV, Hüge W, Schicke B (1987) Beziehung zwischen HLA-DR4-Antigen und röntgenmorphologischer Progredienz bei Rheumatoid-Arthritis. Gesamte Klin Med 42:877–883

    Google Scholar 

  47. Jaraquemada D, Ollier W, Awad J, Young A, Festenstein H (1994) HLA and rheumatoid arthritis: susceptibility or severity? Disease Markers 4:43–46

    Google Scholar 

  48. McMichael AJ, Sasazuki T, McDevitt HO, Payne RO (1977) Increased frequency of HLA-Cw3 and HLA-Dw4 in rheumatoid arthritis. Arthritis Rheum 20:1037–1041

    Google Scholar 

  49. Silman AJ, Reeback J, Jaraquemada D (1986) HLA-DR4 as a predictor of outcome three years after onset of rheumatoid arthritis. Rheumatol Int 6:23–27

    Google Scholar 

  50. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG (1988) The American Rheumatism Association 1987 revised criteria for the classfication of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Google Scholar 

  51. Steinbrocker O, Traeger CH, Batterman RC (1949) Therapeutic criteria in rheumatoid arthritis. JAMA 140:659–662

    Google Scholar 

  52. Wiik A (1989) Delineation of a standard procedure for indirect immunofluorescence detection of ANCA. APMIS 6 [Suppl 3]: 12–13

    Google Scholar 

  53. Terasaki PI (1965) Microdroplet assay for human blood lymphotoxins. In: Amos DB, Van Rood JJ (eds) Histocompatibility testing. National Academy of Sciences, Washington D.C., pp 171

    Google Scholar 

  54. Metzger D, Röther E, Melchers I, Schlesier M, Peter HH (1993) Antigen specificities of autoantibodies against neutrophil cytoplasmic antigens (ANCA) in rheumatoid arthritis (abstract). Immunobiology 189:251

    Google Scholar 

  55. Efthimiou J, Spickett G, Lane D (1991) Antineutrophil cytoplasm antibodies, cystic fibrosis and infection. Lancet 337: 1037–1038

    Google Scholar 

  56. Pudifin DJ, Duursma J, Gathiram V, Jackson TFGH (1993) Serum from patients with invasive amoebiasis has anti-neutrophil cytoplasmic antibody activity (abstract). Clin Exp Immunol 93:33

    Google Scholar 

  57. Juby C, Johnston C, Davies P (1992) Antinuclear and antineutrophil cytoplasmatic antibodies (ANCA) in sera of patients with Felty's syndrome. Br J Rheumatol 31:185–188

    Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, University of Freiburg, Hugstetterstrasse 55, D-79112, Freiburg, Germany

    E. Röther, D. Metzger, B. Lang & H. -H. Peter

  2. Clinical Research Unit for Rheumatology, University of Freiburg, Freiburg, Germany

    I. Melchers

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  1. E. Röther
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  2. D. Metzger
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Röther, E., Metzger, D., Lang, B. et al. Anti-neutrophil cytoplasm antibodies (ANCA) in rheumatoid arthritis: relationship to HLA-DR phenotypes, rheumatoid factor, anti-nuclear antibodies and disease severity. Rheumatol Int 14, 155–161 (1994). https://doi.org/10.1007/BF00579701

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