Skip to main content

Advertisement

SpringerLink
Log in

Anti-TNFα therapy in rheumatoid arthritis and autoimmunity

  • Original Article
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

The aim of the study was to evaluate a panel of autoantibodies in patients affected by rheumatoid arthritis (RA) treated with anti-TNFα blockers, and to consider a different autoantibody induction effect by infliximab and etanercept; and in addition to evaluate in these cases a relationship between antinuclear antibody (ANA) titre and both C-reactive protein (CRP) and Blys levels. Fifty-four patients (8 men, 46 women, mean age 51.4 years, mean duration of disease 13.6 years) affected by refractory RA were treated with anti-TNFα blockers for 12 consecutive months; 43 patients were given infliximab and 11 etanercept. At baseline and every 4 months a panel of autoantibodies consisting of rheumatoid factor, antinuclear, anti-double-stranded DNA, anti-ENA, anti-mitochondrial, anti-thyroid and anti-neutrophil cytoplasmic antibodies (ANCA) was tested. At the same time CRP level was measured. Blys level was determined at baseline and after 1 year in five cases that developed a strong positivity for ANA during infliximab therapy. In 41 cases (95.3%) treated with infliximab, ANA were detected on at least one occasion, and in almost half of these cases the titre was very high, equal to or higher than 1:1.280. On the other hand, patients treated with etanercept presented ANA positivity in a lower percentage of cases and at a low titre. No correlation was found between ANA titre and CRP level; Blys level did not present a constant trend in patients who developed a very high positivity for ANA. Anti-double-stranded DNA, anti-thyroid or ANCA were found only in a few patients, in the absence of a clinical picture indicative of systemic lupus erythematosus, autoimmune thyroiditis or ANCA-associated vasculitis. A different incidence of ANA positivity was found in infliximab- and etanercept-treated RA patients; this finding might be due to the partially different method of inhibition of TNFα between the two drugs. Both CRP and Blys do not seem to participate in this phenomenon. Other autoantibodies were detected in a few patients, but no case of onset of new autoimmune disorders was observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Paulus HE, Wiesner J, Bulpitt KJ, Patnaik M, Law J, Park GS, Wong WK (2002) Autoantibodies in early seropositive rheumatoid arthritis, before and during disease modifying antirheumatic drug treatment. J Rheumatol 29:2513–2520

    CAS  PubMed  Google Scholar 

  2. De Rycke L, Kruithof E, Van Demme N, Hoffman 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 48:1015–1023

    Google Scholar 

  3. 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 43:2383–2390

    Article  CAS  PubMed  Google Scholar 

  4. 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 48:2224–2233

    Article  CAS  PubMed  Google Scholar 

  5. Garcia-Planella E, Domenech E, Esteve-Comas M, Bernal I, Cabre E, Boix J, Gassul MA (2003) Development of antinuclear antibodies and its clinical impact in patients with Crohn’s disease treated with chimeric monoclonal anti-TNF-alpha antibodies (infliximab). Eur J Gastroenterol Hepatol 15:351–354

    Article  CAS  PubMed  Google Scholar 

  6. 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 125:32–39

    Google Scholar 

  7. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340:253–259

    Article  CAS  PubMed  Google Scholar 

  8. Favalli EG, Sinigaglia L, Varenna M, Arnoldi C (2000) Drug-induced lupus following treatment with infliximab in rheumatoid arthritis. Lupus 11:753–755

    Article  Google Scholar 

  9. 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 41:1552–1563

    Article  CAS  PubMed  Google Scholar 

  10. Maini RN, St Clair EW, Breedveld FC, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Hamman 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 354:1932–1939

    Article  CAS  PubMed  Google Scholar 

  11. De Bandt M, Vittecoq O, Descamps V, Le Loet X, Meyer O (2003) Anti-TNF-alpha-induced systemic lupus erythematosus. Clin Rheumatol 22:56–61

    Article  PubMed  Google Scholar 

  12. Klapman JB, Ene-Stroescu D, Becker MA, Hananuer SB (2003) A lupus-like syndrome associated with infliximab therapy. Inflamm Bowel Dis 9:176–178

    Article  PubMed  Google Scholar 

  13. Mohan AK, Edwards ET, Coté TR, Siegel JN, Braun MM (2002) Drug-induced systemic lupus erythematosus and TNF-alpha blockers. Lancet 360:646

    Article  PubMed  Google Scholar 

  14. Shakoor N, Michalska M, Harris CA, Block JA (2002) Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 359:579–580

    Article  CAS  PubMed  Google Scholar 

  15. Carlson E, Rothfield N (2003) Etanercept-induced lupus-like syndrome in a patient with rheumatoid arthritis. Arthritis Rheum 48:1165–1166

    Article  PubMed  Google Scholar 

  16. De Bandt MJ, Descamps V, Meyer O (2001) Two cases of etanercept-induced lupus-like syndrome in RA patients (abstract). Ann Rheum Dis 60(Suppl 1):175

    Google Scholar 

  17. Bleumink GS, ter Borg EJ, Ramselaar CG, Stricker BH (2001) Etanercept-induced subacute cutaneous lupus erythematosus. Rheumatology 40:1317–1319

    Article  CAS  PubMed  Google Scholar 

  18. Swale VJ, Perrett CM, Denton CP, Black CM, Rustin MH (2003) Etanercept-induced systemic lupus erythematosus. Clin Exp Dermatol 28:604–607

    Article  CAS  PubMed  Google Scholar 

  19. Cairns AP, Duncan MK, Hinder AE, Taggart AJ (2002) New onset of systemic lupus erythematosus in a patient receiving etanercept for rheumatoid arthritis. Ann Rheum Dis 61:1031–1032

    Article  CAS  PubMed  Google Scholar 

  20. Brion PH, Mittal-Henkle A, Kalunian KC (1999) Autoimmune skin rashes associated with etanercept for rheumatoid arthritis. Ann Intern Med 131:634

    CAS  PubMed  Google Scholar 

  21. Lepore L, Marchetti F, Facchini S, Leone V, Ventura A (2003) Drug-induced systemic lupus erythematosus associated with etanercept therapy in a child with juvenile idiopathic arthritis. Clin Exp Rheumatol 21:276–277

    CAS  PubMed  Google Scholar 

  22. 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 35:814–817

    Article  CAS  PubMed  Google Scholar 

  23. Hanauer SB (1999) Review article: safety of infliximab in clinical trials. Aliment Pharmacol Ther 13(Suppl 4):16–22

    Article  CAS  PubMed  Google Scholar 

  24. Von Muhlen CA, Tan EM (1995) Antibodies in diagnosis of systemic rheumatic diseases. Semin Arthritis Rheum 24:232–258

    Google Scholar 

  25. Bickerstaff MC, Botto M, Hutchinson WL, Herbert J, Teenant GA, Bybee 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 5:694–697

    Google Scholar 

  26. 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 192:1353–1364

    Article  PubMed  Google Scholar 

  27. Ferraccioli GF, Mecchia F, Di Poi E, Fabris M (2002) Anticardiolipin antibodies in rheumatoid patients treated with etanercept or conventional combination therapy: direct and indirect evidence for a possible association with infections. Ann Rheum Dis 61:358–361

    Article  CAS  PubMed  Google Scholar 

  28. Ioannou Y, Isemberg DA (2000) Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum 43:1431–1442

    Article  CAS  PubMed  Google Scholar 

  29. 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 167:6821–6826

    Google Scholar 

  30. Jacob CO, McDevitt HO (1998) Tumor necrosis factor-α in murine autoimmune ‘lupus’ nephritis. Nature 331:356–358

    Article  Google Scholar 

  31. 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 85:385–391

    Google Scholar 

  32. Pisetsky DS (2000) Tumor necrosis factor α blockers and the induction of anti-DNA antibodies. Arthritis Rheum 43:2381–2382

    Article  CAS  PubMed  Google Scholar 

  33. Mackay F, Browning JL (2002) BAFF: a fundamental survival factor for B cells. Nat Rev Immunol 2:465–475

    Google Scholar 

  34. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA Jr, 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 31:315–324

    CAS  PubMed  Google Scholar 

  35. Nardelli B, Belvedere O, Roschke V, Moore PA, Olsen HS, Migone TS, Sosnovtseva S, Carrell JA, Feng P, Giri JG, Hilbert DM (2001) Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood 97:198–204

    Article  CAS  PubMed  Google Scholar 

  36. Krause I, Valesini G, Scrivo R, Shoenfeld Y (2003) Autoimmune aspects of cytokine and anticytokine therapies. Am J Med 115:390–397

    Article  CAS  PubMed  Google Scholar 

  37. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, Mohler K, Widmer MB, Blosch CM (1997) Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 337:141–147

    Article  CAS  PubMed  Google Scholar 

  38. Fleischmann R, Iqbal I, Nandeshwar P, Quiceno A (2000) Safety and efficacy of disease-modifying anti-rheumatic agents. Drug Safety 25:173–197

    Google Scholar 

  39. Drosos AA (2002) Newer immunosuppressive drugs. Their potential role in rheumatoid arthritis therapy. Drugs 62:891–907

    CAS  PubMed  Google Scholar 

  40. Andrade F, Casciola-Rosen L, Rosen A (2000) Apoptosis in systemic lupus erythematosus. Clinical implications. Rheum Dis North Am 26:215–227

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Medicina Clinica e Sperimentale, Università di Verona, Verona, Italy

    Paola Caramaschi, Domenico Biasi, Sara Pieropan, Nicola Martinelli, Antonio Carletto, Alessandro Volpe, Luisa Maria Pacor & Lisa Maria Bambara

  2. Dipartimento di Patologia, Università di Verona, Verona, Italy

    Marco Colombatti

Authors
  1. Paola Caramaschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Domenico Biasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Colombatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara Pieropan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicola Martinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Carletto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alessandro Volpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luisa Maria Pacor
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lisa Maria Bambara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paola Caramaschi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Caramaschi, P., Biasi, D., Colombatti, M. et al. Anti-TNFα therapy in rheumatoid arthritis and autoimmunity. Rheumatol Int 26, 209–214 (2006). https://doi.org/10.1007/s00296-004-0542-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-004-0542-1

Keywords

Search

Navigation