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Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2005 Apr 20;64(10):1414–1420. doi: 10.1136/ard.2004.033241

Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists

J Askling 1, C Fored 1, E Baecklund 1, L Brandt 1, C Backlin 1, A Ekbom 1, C Sundstrom 1, L Bertilsson 1, L Coster 1, P Geborek 1, L Jacobsson 1, S Lindblad 1, J Lysholm 1, S Rantapaa-Dahlqvis 1, T Saxne 1, L Klareskog 1, N Feltelius 1
PMCID: PMC1755232  PMID: 15843454

Abstract

Background: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear.

Objective: To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA.

Methods: A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53 067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed.

Results: Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas.

Conclusion: Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.

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Selected References

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  1. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  2. Askling J., Fored C. M., Brandt L., Baecklund E., Bertilsson L., Feltelius N., Cöster L., Geborek P., Jacobsson L. T., Lindblad S. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis. 2005 Apr 13;64(10):1421–1426. doi: 10.1136/ard.2004.033993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baecklund E., Ekbom A., Sparén P., Feltelius N., Klareskog L. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ. 1998 Jul 18;317(7152):180–181. doi: 10.1136/bmj.317.7152.180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baecklund Eva, Sundström Christer, Ekbom Anders, Catrina Anca I., Biberfeld Peter, Feltelius Nils, Klareskog Lars. Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma. Arthritis Rheum. 2003 Jun;48(6):1543–1550. doi: 10.1002/art.11144. [DOI] [PubMed] [Google Scholar]
  5. Bendix G., Bjelle A., Holmberg E. Cancer morbidity in rheumatoid arthritis patients treated with Proresid or parenteral gold. Scand J Rheumatol. 1995;24(2):79–84. doi: 10.3109/03009749509099289. [DOI] [PubMed] [Google Scholar]
  6. Bickston S. J., Lichtenstein G. R., Arseneau K. O., Cohen R. B., Cominelli F. The relationship between infliximab treatment and lymphoma in Crohn's disease. Gastroenterology. 1999 Dec;117(6):1433–1437. doi: 10.1016/s0016-5085(99)70294-5. [DOI] [PubMed] [Google Scholar]
  7. Brown S. Lori, Greene Mark H., Gershon Sharon K., Edwards Evelyne T., Braun M. Miles. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum. 2002 Dec;46(12):3151–3158. doi: 10.1002/art.10679. [DOI] [PubMed] [Google Scholar]
  8. Cibere J., Sibley J., Haga M. Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum. 1997 Sep;40(9):1580–1586. doi: 10.1002/art.1780400906. [DOI] [PubMed] [Google Scholar]
  9. Danesi R., Del Tacca M. Hematologic toxicity of immunosuppressive treatment. Transplant Proc. 2004 Apr;36(3):703–704. doi: 10.1016/j.transproceed.2004.03.016. [DOI] [PubMed] [Google Scholar]
  10. Ekström Karin, Hjalgrim Henrik, Brandt Lena, Baecklund Eva, Klareskog Lars, Ekbom Anders, Askling Johan. Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. Arthritis Rheum. 2003 Apr;48(4):963–970. doi: 10.1002/art.10939. [DOI] [PubMed] [Google Scholar]
  11. Feltelius N., Fored C. M., Blomqvist P., Bertilsson L., Geborek P., Jacobsson L. T., Lindblad S., Lysholm J., Rantapä-Dahlqvist S., Saxne T. Results from a nationwide postmarketing cohort study of patients in Sweden treated with etanercept. Ann Rheum Dis. 2004 Jun 18;64(2):246–252. doi: 10.1136/ard.2004.023473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Geborek P., Bladström A., Turesson C., Gulfe A., Petersson I. F., Saxne T., Olsson H., Jacobsson L. T. H. Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis. 2005 Feb 4;64(5):699–703. doi: 10.1136/ard.2004.030528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gridley G., Klippel J. H., Hoover R. N., Fraumeni J. F., Jr Incidence of cancer among men with the Felty syndrome. Ann Intern Med. 1994 Jan 1;120(1):35–39. doi: 10.7326/0003-4819-120-1-199401010-00006. [DOI] [PubMed] [Google Scholar]
  14. Gridley G., McLaughlin J. K., Ekbom A., Klareskog L., Adami H. O., Hacker D. G., Hoover R., Fraumeni J. F., Jr Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst. 1993 Feb 17;85(4):307–311. doi: 10.1093/jnci/85.4.307. [DOI] [PubMed] [Google Scholar]
  15. Hakulinen T., Isomaki H., Knekt P. Rheumatoid arthritis and cancer studies based on linking nationwide registries in Finland. Am J Med. 1985 Jan 21;78(1A):29–32. doi: 10.1016/0002-9343(85)90242-6. [DOI] [PubMed] [Google Scholar]
  16. Herrick A. L., McColl K. E. Lack of certainty on the diagnosis of acute intermittent porphyria: comment on the concise communication by Cohen et al. Arthritis Rheum. 1998 Jan;41(1):188–189. doi: 10.1002/1529-0131(199801)41:1<188::AID-ART34>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  17. Kamel O. W., Holly E. A., van de Rijn M., Lele C., Sah A. A population based, case control study of non-Hodgkin's lymphoma in patients with rheumatoid arthritis. J Rheumatol. 1999 Aug;26(8):1676–1680. [PubMed] [Google Scholar]
  18. Kauppi M., Pukkala E., Isomäki H. Elevated incidence of hematologic malignancies in patients with Sjögren's syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control. 1997 Mar;8(2):201–204. doi: 10.1023/a:1018472213872. [DOI] [PubMed] [Google Scholar]
  19. Knowles D. M. Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol. 1999 Feb;12(2):200–217. [PubMed] [Google Scholar]
  20. Ljung T., Karlén P., Schmidt D., Hellström P. M., Lapidus A., Janczewska I., Sjöqvist U., Löfberg R. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut. 2004 Jun;53(6):849–853. doi: 10.1136/gut.2003.018515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mattsson B., Wallgren A. Completeness of the Swedish Cancer Register. Non-notified cancer cases recorded on death certificates in 1978. Acta Radiol Oncol. 1984;23(5):305–313. doi: 10.3109/02841868409136026. [DOI] [PubMed] [Google Scholar]
  22. Mellemkjaer L., Linet M. S., Gridley G., Frisch M., Møller H., Olsen J. H. Rheumatoid arthritis and cancer risk. Eur J Cancer. 1996 Sep;32A(10):1753–1757. doi: 10.1016/0959-8049(96)00210-9. [DOI] [PubMed] [Google Scholar]
  23. Moder K. G., Tefferi A., Cohen M. D., Menke D. M., Luthra H. S. Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study. Am J Med. 1995 Sep;99(3):276–281. doi: 10.1016/s0002-9343(99)80160-0. [DOI] [PubMed] [Google Scholar]
  24. Myllykangas-Luosujärvi R., Aho K., Isomäki H. Mortality from cancer in patients with rheumatoid arthritis. Scand J Rheumatol. 1995;24(2):76–78. doi: 10.3109/03009749509099288. [DOI] [PubMed] [Google Scholar]
  25. Prior P., Symmons D. P., Hawkins C. F., Scott D. L., Brown R. Cancer morbidity in rheumatoid arthritis. Ann Rheum Dis. 1984 Apr;43(2):128–131. doi: 10.1136/ard.43.2.128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Symmons D. P. Neoplasms of the immune system in rheumatoid arthritis. Am J Med. 1985 Jan 21;78(1A):22–28. doi: 10.1016/0002-9343(85)90241-4. [DOI] [PubMed] [Google Scholar]
  27. Söderlin M. K., Börjesson O., Kautiainen H., Skogh T., Leirisalo-Repo M. Annual incidence of inflammatory joint diseases in a population based study in southern Sweden. Ann Rheum Dis. 2002 Oct;61(10):911–915. doi: 10.1136/ard.61.10.911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Thomas E., Brewster D. H., Black R. J., Macfarlane G. J. Risk of malignancy among patients with rheumatic conditions. Int J Cancer. 2000 Nov 1;88(3):497–502. [PubMed] [Google Scholar]
  29. Wolfe Frederick, Michaud Kaleb. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum. 2004 Jun;50(6):1740–1751. doi: 10.1002/art.20311. [DOI] [PubMed] [Google Scholar]

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