Skip to main content

Advertisement

SpringerLink
Log in

Malignancies and anti-TNF therapy in rheumatoid arthritis: a single-center observational cohort study

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

Abstract

Inhibitors of tumor necrosing factor alpha (TNF-a) have proven to be highly effective in the treatment of rheumatoid arthritis (RA). Concerns, however, are raised about the possible association between these treatments and an increased development of malignancies. The objective of this paper was to compare the risk of hematologic and solid malignancies in patients treated for RA with anti-TNF therapy, with the risk in the general population. From January 2000 until January 2012, all RA patients that started treatment with anti-TNF agents were included in this single-center cohort study. The primary outcome of this study was the incidence of malignancy after starting anti-TNF treatment. In our cohort of 365 patients, 34 malignancies were discovered in 30 patients after the start of anti-TNF treatment; 20 patients developed a solid malignancy, 6 a hematologic, 2 a solid and a hematologic malignancy, and 2 patients developed 2 solid malignancies. The overall incidence rate (IR) of malignancy was 1379.1 per 100.000 patient years. The risk or standardized incidence ratio (SIR) of solid malignancy, calculated by comparison with the age-adjusted population in Flanders, was 120.1 in female and 136.7 in male patients. The calculated SIR of hematologic malignancy was 450.8 for women and 473.9 for men. Some immune modulation-related lymphoproliferative disorders regressed spontaneously when stopping TNF blockers. Overall, the malignancy risk in our rheumatoid arthritis patients treated with anti-TNF therapy was slightly higher than in the normal population; the risk of hematologic malignancies was more important.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Scott DL, Wolfe F, Huizinga TWJ (2010) Rheumatoid arthritis. Lancet 376:1094–1108

    Article  PubMed  Google Scholar 

  2. Pedersen JK, Kjaer NK, Svendsen AJ, Horslev-Petersen K (2009) Incidence of rheumatoid arthritis from 1995 to 2001: impact of ascertainment from multiple sources. Rheumatol Int 29:411–415

    Article  PubMed  Google Scholar 

  3. Colmegna I, Ohata BR, Menard HA (2012) Current understanding of rheumatoid arthritis therapy. ClinPharmacolTher 4:607–620

    Google Scholar 

  4. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. PharmacolTher 117:244–279

    CAS  Google Scholar 

  5. Scott DL (2012) Biologics-based therapy for the treatment of rheumatoid arthritis. ClinPharmacolTher 91:30–43

    CAS  Google Scholar 

  6. Raval G, Mehta P (2010) TNF-a inhibitors: are they carcinogenic? Drug Health Patient Saf 2:241–247

    CAS  Google Scholar 

  7. Smitten AL, Simon TA, Hochberg MC, Suissa S (2008) A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther 10:R45

    Article  PubMed Central  PubMed  Google Scholar 

  8. Heminki K, Sundquist K, Sundquist J (2008) Cancer risk in hospitalized rheumatoid arthritis patients. Rheumatology 47:698–701

    Article  Google Scholar 

  9. Keystone EC (2011) Does Anti-tumour necrosis factor alfa therapy affect risk of serious infection and cancer in patients with rheumatoid arthritis? A review of longterm data. J Rheumatol 38:1552–1562

    Article  CAS  PubMed  Google Scholar 

  10. Ekström K, Hjalgrim H, Brandt L, Baecklund E, Klareskog L, Ekbom A, Askling J (2003) Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. Arthritis Rheum 48:963–970

    Article  PubMed  Google Scholar 

  11. Setoguchi S, Solomon DH, Weinblatt ME, Katz JN, Avorn J, Glynn RJ, Cook EF, Carney G, Schneeweiss S (2006) Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum 54:2757–2764

    Article  CAS  PubMed  Google Scholar 

  12. Krathen MS, Gottlieb AB, Mease PJ (2010) Pharmacologic Immunomodulation and Cutaneous Malignancy in Rheumatoid Arthritis, Psoriasis, and Psoriatic Arthritis. J Rheumatol 37:2205–2215

    Article  CAS  PubMed  Google Scholar 

  13. Burmester GR, Mease P, Dijkmans BA, Gordon K, Lovell D, Panaccione R, Perez J, Pangan AL (2009) Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis 68:1863–1869

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Solomon DH, Mercer E, Kavanaugh A (2012) Observational Studies on the Risk of Cancer Associated With Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis. Arthritis Rheum 64:21–32

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Rosenblum H, Amital H (2011) Anti-TNF therapy: safety aspects of taking the risk. Autoimmun Rev 10:563–568

    Article  PubMed  Google Scholar 

  16. Mariette X, Matucci-Cerinic M, Pavelka K, Taylor P, van Vollenhoven R, Heatley R, Walsh C, Lawson R, Reynolds A, Emery P (2011) Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis 70:1895–1904

    Article  PubMed  Google Scholar 

  17. Wolfe F, Michaud K (2007) The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum 56:1433–1439

    Article  CAS  PubMed  Google Scholar 

  18. Wolfe F, Michaud K (2007) Biologic treatment of Rheumatoid Arthritis and the risk of malignancy. Arthritis Rheum 56:2886–2895

    Article  PubMed  Google Scholar 

  19. Nasir A, Greenberg JD (2007) TNF antagonist safety in rheumatoid arthritis. updated evidence from observational registries. Bull NYU HospJt Dis 65:178–181

    Google Scholar 

  20. Strangfeld A, Hierse F, Rau R, Burmester GR, Krummel-Lorenz B, Demary W, Listing J, Zink A (2010) Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT. Arthritis Res Ther 12:R5

    Article  PubMed Central  PubMed  Google Scholar 

  21. Le Blay P, Mouterde G, Barnetche T, Morel J, Combe B (2012) Risk of malignancy including non-melanoma skin cancers with anti-tumor necrosis factor therapie in patients with rheumatoid arthritis: a meta-analysis of registries and systematic review of long-term extension studies. ClinExpRheumatol 30:756–764

    Google Scholar 

  22. Dreyer L, Mellemkjær L, Rødgaard Andersen A, Bennett P, EnglingPoulsen U, JuulsgaardEllingsen T, Høiland Hansen T, Vendelbo Jensen D, Linde L, Merete Lindegaard H, Rasmussen Loft AG, Nordin H, Omerovic E, Rasmussen C, Schlemmer A, Tarp U, Lund Hetland M (2013) Incidences of overall and site specific cancers in TNFα inhibitor treated patients with rheumatoid arthritis and other arthritides – a follow-up study from the DANBIO. Ann Rheum Dis 72:79–82

    Article  PubMed  Google Scholar 

  23. Horton S, Buch MH, Emery P (2010) Efficacy, tolerability and safety of biologic therapy in rheumatoid disease: patient considerations. Drug Healthc Patient Saf 2:101–119

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Mercer LK, Green AC, Galloway JB, Davies R, Lunt M, Dixon WG, Watson KD, British Society for Rheumatology Biologics Register Control Centre Consortiom DP Symmons KL Hyrich British Society for Rheumatology Biologics Register (2012) The influence of anti-TNF therapy upon incidence of keratinocyte skin cancer in patients with rheumatoid arthritis: longitudinal results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 71:869–874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF Antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA 295:2275–2285

    Article  CAS  PubMed  Google Scholar 

  26. http://www.kankerregister.org/

  27. Silcocks P (1994) Estimating confidence limits on a standardised mortality ratio when the expected number is not error free. J Epidemiol Community Health 48:313–317

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, Catrina AI, Rosenquist R, Feltelius N, Sundström C, Klareskog L (2006) Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 54:692–701

    Article  PubMed  Google Scholar 

  29. Mariette X, Gottenberg JE, Ravaud P, Combe B (2011) Registries in rheumatoid arthritis and auto-immune diseases: data from the French registries. Rheumatology 50:222–229

    Article  PubMed  Google Scholar 

  30. Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, Wagner C (2002) Binding and functional comparisons of two types of tumor necrosis factor antagonists. J PharmacolExpTher 301:418–426

    CAS  Google Scholar 

  31. Hasserjian RP, Chen S, Perkins SL, de Leval L, Kinney MC, Barry TS, Said J, Lim MS, Finn WG, Medeiros LJ, Harris NL, O’Malley DP (2009) Immunomodulator agent-related lymphoproliferative disorders. Mod Pathol 22:1532–1540

    Article  CAS  PubMed  Google Scholar 

  32. Ichikawa A, Arakawa F, Kiyasu J, Sato K, Miyoshi H, Niino D, Kimura Y, Takeuchi M, Yoshida M, Ishibashi Y, Nakashima S, Sugita Y, Miura O, Ohshima K (2013) Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression. Eur J Haematol 91:20–28

    Article  CAS  PubMed  Google Scholar 

  33. Knowles DM (1999) Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol 12:200–217

    CAS  PubMed  Google Scholar 

  34. Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, Brepoels L, Kuypers D, Vanhaecke J, Nevens F, Verleden G, Van Damme-Lombaerts R, Renard M, Pirenne J, De Wolf-Peeters V, Verhoef G (2013) Single-center analysis of biopsy-confirmed post-transplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. Leuk Lymphoma 54:2433–2440

    Article  PubMed  Google Scholar 

  35. Feng W, Cohen J, Fischer S, Li L, Sneller M, Goldbach-Mansky R, Raab-Traub N, Delecluse H, Kenney S (2004) Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. J Natl Cancer Inst 96:1691–1702

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Patricia Berghman for her administrative support, Dirk Teuwen for his critical comments, and Flip Van Oyen for his IT support.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Nathalie Berghen and Laure-Anne Teuwen collected, analyzed and interpreted the data and drafted the manuscript. Patrick Verschueren and Rene Westhovens participated in the design of the study, interpreted the data and revised the manuscript critically. All authors read and approved the final manuscript.

The study was approved by the local Ethical Committee: the Medical Ethical Committee of the Leuven University Hospital.

Author information

Author notes

    Authors and Affiliations

    1. Department of Rheumatology, University Hospitals Leuven, Leuven, Herestraat 49, 3000, Leuven, Belgium

      Nathalie Berghen, Laure-Anne Teuwen, Rene Westhovens & Patrick Verschueren

    Authors
    1. Nathalie Berghen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Laure-Anne Teuwen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Rene Westhovens
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Patrick Verschueren
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Laure-Anne Teuwen or Patrick Verschueren.

    Additional information

    Nathalie Berghen and Laure-Anne Teuwen contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    ESM 1

    (PDF 399 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Berghen, N., Teuwen, LA., Westhovens, R. et al. Malignancies and anti-TNF therapy in rheumatoid arthritis: a single-center observational cohort study. Clin Rheumatol 34, 1687–1695 (2015). https://doi.org/10.1007/s10067-015-3026-7

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10067-015-3026-7

    Keywords

    Search

    Navigation