Rheumatology International

, Volume 26, Issue 1, pp 58–62 | Cite as

Antibodies against cyclic citrullinated peptides in patients affected by rheumatoid arthritis before and after infliximab treatment

  • Paola CaramaschiEmail author
  • Domenico Biasi
  • Elisabetta Tonolli
  • Sara Pieropan
  • Nicola Martinelli
  • Antonio Carletto
  • Alessandro Volpe
  • Lisa Maria Bambara
Original Article


To evaluate antibodies against cyclic citrullinated peptides (anti-CCP) together with rheumatoid factor (RF), antinuclear antibodies (ANA) and C-reactive protein (CRP), in patients affected by rheumatoid arthritis (RA), before and after infliximab treatment. Twenty-seven patients (five men and 22 women, mean age of 51.9 years, mean duration of disease 12.6 years) affected by RA, refractory to conventional DMARDs, were treated with infliximab, at the conventional dosage. Before starting infliximab and after 22 weeks, on the occasion of the fifth infusion, anti-CCP antibodies were tested by ELISA method. At the same time IgM RF, ANA and CRP level were measured. Before infliximab therapy, anti-CCP antibodies resulted positive in 23 patients (85.1%); the serum level did not change after infliximab treatment; only one case negative at baseline became slightly positive after treatment. Before and after therapy RF resulted positive in 22 cases (81.4%) and 21 cases (77.7%) respectively; comparing values at baseline with those after 22 weeks of treatment with infliximab, RF levels significantly decreased, as well as CRP values. In contrast to both anti-CCP antibodies, which remained stable, and to RF, which fell after infliximab, ANA were positive ≥ 1: 160 in four cases at baseline and in 12 after treatment. The titre of anti-CCP antibodies did not significantly change after anti-TNFα blocker administration; instead the positivity of RF significantly decreased. As opposed to antinuclear and anti-dsDNA antibodies, which may appear or increase in titre during infliximab treatment, the typical autoantibodies detectable in RA show a different trend; in fact, anti-CCP antibodies remained stable and RF decreased.


Antibodies anti-cyclic citrullinated peptides Rheumatoid arthritis Infliximab 


  1. 1.
    Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 343:1594–1602CrossRefPubMedGoogle Scholar
  2. 2.
    Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF, Feldmann M (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 41:1552–1563CrossRefPubMedGoogle Scholar
  3. 3.
    De Rycke L, Kruithof E, Van Damme N, Hoffmann IEA, Van den Bossche N, Van den Bosch F, Veys EM, De Keyser F (2003) Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondyloarthropathy. Arthritis Rheum 48:105–123Google Scholar
  4. 4.
    Charles PJ, Smeenk RJT, De Jong J, Feldmann M, Maini RN (2000) Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor α. Arthritis Rheum 43:2383–2390CrossRefPubMedGoogle Scholar
  5. 5.
    Braun J, Brandt J, Listing J, Zink A, Alten R, Burmester G, Golder W, Gromnica-Ihle E, Kellner H, Schneider M, Sorensen H, Zeidler H, Reddig J, Sieper J (2003) Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis. Arthritis Rheum 48:2224–2233CrossRefPubMedGoogle Scholar
  6. 6.
    Garcia-Planella E, Domenech E, Esteve-Comas M, Bernal I, Cabre E, Boix J, Gassull MA (2003) Development of antinuclear antibodies and its clinical impact in patients with Crohn’s disease treated with chimeric monoclonal anti-TNFalpha antibodies (infliximab). Eur J Gastroenterol Hepatol 15:351–354CrossRefPubMedGoogle Scholar
  7. 7.
    Vermeire S, Noman M, Van Assche G, Baert F, Van Steen K, Esters N, Joossens S, Bossuyt X, Rutgeerts P (2003) Autoimmunity associated with anti-tumor necrosis factor α treatment in Crohn’s disease: a prospective cohort study. Gastroenterology 125:32–39Google Scholar
  8. 8.
    Favalli EG, Sinigaglia L, Varenna M, Arnoldi C (2000) Drug-induced lupus following treatment with infliximab in rheumatoid arthritis. Lupus 11:753–755CrossRefGoogle Scholar
  9. 9.
    Maini RN, St Clair EW, Breedveld FC, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P (1999) Infliximab (chimeric anti-tumor necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet 354:1932–1939CrossRefPubMedGoogle Scholar
  10. 10.
    De Bandt M, Vittecoq O, Descamps V, Le Loet X, Meyer O (2003) Anti-TNF-alpha-induced systemic lupus erythematosus. Clin Rheumatol 22:56–61CrossRefPubMedGoogle Scholar
  11. 11.
    Klapman JB, Ene-Stroescu D, Becker MA, Hananuer SB (2003) A lupus-like syndrome associated with infliximab therapy. Inflamm Bowel Dis 9:176–178CrossRefPubMedGoogle Scholar
  12. 12.
    Mohan AK Edwards ET, Coté TR, Siegel JN, Braun MM (2002) Drug-induced systemic lupus erythematosus and TNF-alpha blockers. Lancet 360:646CrossRefPubMedGoogle Scholar
  13. 13.
    Sarzi-Puttini P, Ardizzone S, Manzionna G, Atzeni F, Colombo E, Antivalle M, Carrabba M, Bianchi-Porro G (2003) Infliximab-induced lupus in Crohn’s disease: a case report. Dig Liver Dis 35:814–817CrossRefPubMedGoogle Scholar
  14. 14.
    Hanauer SB (1999) Review article: safety of infliximab in clinical trials. Aliment Pharmacol Ther 13(Suppl 4):16–22CrossRefPubMedGoogle Scholar
  15. 15.
    Shakoor N, Michalska M, Harris CA, Block JA (2002) Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 359:579–580CrossRefPubMedGoogle Scholar
  16. 16.
    Carlson E, Rothfield N (2003) Etanercept-induced lupus-like syndrome in a patient with rheumatoid arthritis. Arthritis Rheum 48:1165–1166CrossRefPubMedGoogle Scholar
  17. 17.
    De Bandt MJ, Descamps V, Meyer O (2001) Two cases of etanercept-induced lupus-like syndrome in RA patients. Ann Rheum Dis 60(Suppl 1):175Google Scholar
  18. 18.
    Bleumink GS, ter Borg EJ, Ramselaar CG, Stricker BH (2001) Etanercept-induced subacute cutaneous lupus erythematosus. Rheumatology 40:1317–1319CrossRefPubMedGoogle Scholar
  19. 19.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA Jr, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324PubMedGoogle Scholar
  20. 20.
    Suzuki K, Sawada T, Murakami A, Matsui T, Tohma S, Nakazono K, Takemura S, Takasaki Y, Mimori T, Yamamoto K (2003) High diagnostic performance of ELISA detection of antibodies to citrullinated antigens in rheumatoid arthritis. Scand J Rheumatol 32:197–204Google Scholar
  21. 21.
    Lee DM, Schur PH (2003) Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 62:870–874Google Scholar
  22. 22.
    Zeng X, Ai M, Tian X, Gan X, Shi Y, Song Q, Tang F (2003) Diagnostic value of anti-cyclic citrullinated peptide antibody in patients with rheumatoid arthritis. J Rheumatol 30:1451–1455Google Scholar
  23. 23.
    Schellekens GA, Visser H, de Jong BAW, van den Hoogen FHJ, Hazes JMW, Breedveld FC, van Venrooij WJ (2000) The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43:155–163Google Scholar
  24. 24.
    Schellekens GA, de Jong BAW, van den Hoogen FHJ, van de Putte LB, van Venrooij WJ (1998) Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 101:273–281PubMedGoogle Scholar
  25. 25.
    Kroot EJA, de Jong BAW, van Leeuwen MA, Swinkels H, van den Hoogen FHJ, van’t Hof M, van de Putte LBA, van Rijswijk MH, van Venrooij WJ, van Riel PLCM (2000) The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 43:1831–1835CrossRefPubMedGoogle Scholar
  26. 26.
    Cambridge G, Leandro MJ, Edwards JCW, Ehrenstein MR, Salden M, Bodman-Smith M, Webster ADB (2003) Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 48:2146–2154Google Scholar
  27. 27.
    Bickerstaff MC, Botto M, Hutchinson WL, Herbert J, Tennent GA, Bybe A, Mitchell DA, Cook HT, Butler PJ, Walport MJ, Pepys MB (1999) Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5:694–697Google Scholar
  28. 28.
    Gershow D, Kim S, Brot N, Elkon KB (2000) C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J Exp Med 192:1353–1364CrossRefPubMedGoogle Scholar
  29. 29.
    Ioannou Y, Isemberg DA (2000) Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum 43:1431–1442CrossRefPubMedGoogle Scholar
  30. 30.
    Via CS, Shustov A, Rus V, Lang T, Nguyen P, Finkelman FD (2001) In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL. J Immunol 167:6821–6826Google Scholar
  31. 31.
    Jacob CO, McDevitt HO (1988) Tumor necrosis factor-α in murine autoimmune ‘lupus’ nephritis. Nature 331:356–358Google Scholar
  32. 32.
    Mitamura K, Kang H, Tomita J, Hashimoto H, Sawada S, Horie T (1991) Impaired tumour necrosis factor-alpha (TNF-alpha) production and abnormal B cell response to TNF-alpha in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 85:385–391Google Scholar
  33. 33.
    Pisetsky DS (2000) Tumor necrosis factor α blockers and the induction of anti-DNA antibodies. Arthritis Rheum 43:2381–2382CrossRefPubMedGoogle Scholar
  34. 34.
    Vossenaar ER, Nijenhuis S, Helsen MM, van der Heijden A, Senshu T, van der Berg WB, van Venroij WJ, Joosten LA (2003) Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 48:2489–2500Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Paola Caramaschi
    • 1
    Email author
  • Domenico Biasi
    • 1
  • Elisabetta Tonolli
    • 2
  • Sara Pieropan
    • 1
  • Nicola Martinelli
    • 1
  • Antonio Carletto
    • 1
  • Alessandro Volpe
    • 1
  • Lisa Maria Bambara
    • 1
  1. 1.Dipartimento di Medicina Clinica e Sperimentale, Istituto Medicina Interna BUniversità di VeronaVeronaItaly
  2. 2.Servizio di MicrobiologiaUniversitá di VeronaVeronaItaly

Personalised recommendations