Clinical Rheumatology

, Volume 34, Issue 7, pp 1195–1202 | Cite as

The age–risk relationship of hematologic malignancies in patients with rheumatoid arthritis: a nationwide retrospective cohort study

  • Yu-Chih Lin
  • Hui-Wen Chou
  • Wen-Chan Tsai
  • Jeng-Hsien Yen
  • Shun-Jen ChangEmail author
  • Yi-Ching LinEmail author
Original Article


The risk of hematologic malignancies in rheumatoid arthritis (RA) patients has been an important clinical concern. The information of age effect on the interval from the diagnosis of RA to that of hematologic malignancies is limited. This study aimed to define the age–risk relationship between hematologic malignancies and RA. A retrospective cohort study was conducted nationwide with 17,472 patients and 87,360 controls from the Taiwan National Health Insurance Database covering 1997–2008. The subsequent development of hematologic malignancy was observed. The age-adjusted standardized incidence ratios (SIRs), incidence per 1000 person-years, follow-up duration for the diagnosis of hematologic malignancies, and cumulative hazard rates of hematologic malignancies between RA and controls were analyzed. Significantly higher incidences of both lymphoid and myeloid malignancies were found in male RA patients compared with RA-free patients (SIR 3.36, 95 % CI = 2.03–5.57, and SIR: 3.69, 95 % CI = 2.46–5.53). A significantly increased overall incidence risk was found in lymphoid malignancies (SIR 3.00, 95 % CI = 2.22–4.05) but not significantly increased in myeloid malignancies (SIR 1.54, 95 % CI = 0.95–2.50) in female RA. The follow-up duration for hematologic malignancies was significantly shorter in RA patients than in RA-free patients in both males and females (70.70 vs. 103.80 months and 67.73 vs. 100.93 months, respectively). Additionally, higher cumulative hazard rates in both lymphoid and myeloid malignancies were found in male RA patients (p < 0.0001). RA patients have a shorter incubation time to hematological malignancies while comparing to the RA-free people, and the risks are variable in gender and different age groups.


Age risk Autoimmune disease Cancer Hematologic malignancy Rheumatoid arthritis 



The authors thank the help from the Statistical Analysis Laboratory, Department of Internal Medicine, Kaohsiung Medical University Hospital. This study was supported by a grant from Kaohsiung Medical University Hospital (KMUH101-1 M20).




  1. 1.
    Varoczy L, Gergely L, Zeher M, Szegedi G, Illes A (2002) Malignant lymphoma-associated autoimmune diseases—a descriptive epidemiological study. Rheumatol Int 22(6):233–237PubMedCrossRefGoogle Scholar
  2. 2.
    Zintzaras E, Voulgarelis M, Moutsopoulos HM (2005) The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med 165(20):2337–2344PubMedCrossRefGoogle Scholar
  3. 3.
    Bernatsky S, Ramsey-Goldman R, Clarke A (2006) Malignancy and autoimmunity. Curr Opin Rheumatol 18(2):129–134PubMedCrossRefGoogle Scholar
  4. 4.
    Racanelli V, Prete M, Minoia C, Favoino E, Perosa F (2008) Rheumatic disorders as paraneoplastic syndromes. Autoimmun Rev 7(5):352–358PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson LA, Pfeiffer RM, Landgren O, Gadalla S, Berndt SI, Engels EA (2009) Risks of myeloid malignancies in patients with autoimmune conditions. Br J Cancer 100(5):822–828PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Anderson LA, Gadalla S, Morton LM, Landgren O, Pfeiffer R, Warren JL, Berndt SI, Ricker W, Parsons R, Engels EA (2009) Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies. Int J Cancer J Int Cancer 125(2):398–405CrossRefGoogle Scholar
  7. 7.
    Wolfe F, Michaud K (2004) Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 50(6):1740–1751PubMedCrossRefGoogle Scholar
  8. 8.
    Ellman MH, Hurwitz H, Thomas C, Kozloff M (1991) Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. J Rheumatol 18(11):1741–1743PubMedGoogle Scholar
  9. 9.
    Gono T, Shimojima Y, Hoshi K, Yamamoto K, Tokuda T, Shikama N, Matsuda M, Ikeda S (2004) Malignant lymphoma associated with rheumatoid arthritis, developing shortly after initiation of oral methotrexate. Intern Med (Tokyo, Japan) 43(2):135–138CrossRefGoogle Scholar
  10. 10.
    Askling J, Baecklund E, Granath F, Geborek P, Fored M, Backlin C, Bertilsson L, Coster L, Jacobsson LT, Lindblad S, Lysholm J, Rantapaa-Dahlqvist S, Saxne T, van Vollenhoven R, Klareskog L, Feltelius N (2009) Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register. Ann Rheum Dis 68(5):648–653PubMedCrossRefGoogle Scholar
  11. 11.
    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(11):1895–1904PubMedCrossRefGoogle Scholar
  12. 12.
    Symmons DP, Silman AJ (2004) Anti-tumor necrosis factor alpha therapy and the risk of lymphoma in rheumatoid arthritis: no clear answer. Arthritis Rheum 50(6):1703–1706PubMedCrossRefGoogle Scholar
  13. 13.
    Fleischmann RM, Iqbal I, Stern RL (2004) Considerations with the use of biological therapy in the treatment of rheumatoid arthritis. Expert Opin Drug Saf 3(5):391–403PubMedCrossRefGoogle Scholar
  14. 14.
    Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L (1998) Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ (Clinical research ed) 317(7152):180–181CrossRefGoogle Scholar
  15. 15.
    Newkirk M, Shiroky J, Johnson N, Danoff D, Isenberg D, Shustik C, Pearson G (1996) Rheumatic disease patients, prone to Sjögren’s syndrome and/or lymphoma, mount an antibody response to BHRF1, the Epstein-Barr viral homologue of BCL-2. Rheumatology 35(11):1075–1081CrossRefGoogle Scholar
  16. 16.
    Kamel OW, van de Rijn M, Weiss LM, Del Zoppo GJ, Hench PK, Robbins BA, Montgomery PG, Warnke RA, Dorfman RF (1993) Reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 328(18):1317–1321PubMedCrossRefGoogle Scholar
  17. 17.
    van de Rijn M, Cleary ML, Variakojis D, Warnke RA, Chang PP, Kamel OW (1996) Epstein-Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis. Arthritis Rheum 39(4):638–642PubMedCrossRefGoogle Scholar
  18. 18.
    Kamel O, Holly E, Van de Rijn M, Lele C, Sah A (1999) A population based, case control study of non-Hodgkin’s lymphoma in patients with rheumatoid arthritis. J Rheumatol 26(8):1676PubMedGoogle Scholar
  19. 19.
    Lin YC, Yen JH, Chang SJ, Lin YC (2012) The age-risk relationship of haematologic malignancies in female patients with systemic lupus erythematosus: a nationwide retrospective cohort study. Lupus 21(11):1250–1256PubMedCrossRefGoogle Scholar
  20. 20.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324PubMedCrossRefGoogle Scholar
  21. 21.
    Chen YJ, Chang YT, Wang CB, Wu CY (2011) The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan. Arthritis Rheum 63(2):352–358PubMedCrossRefGoogle Scholar
  22. 22.
    Huang WK, Chiou MJ, Kuo CF, Lin YC, Yu KH, See LC (2014) No overall increased risk of cancer in patients with rheumatoid arthritis: a nationwide dynamic cohort study in Taiwan. Rheumatol Int 34(10):1379–1386PubMedCrossRefGoogle Scholar
  23. 23.
    Hellgren K, Smedby KE, Feltelius N, Baecklund E, Askling J (2010) Do rheumatoid arthritis and lymphoma share risk factors?: a comparison of lymphoma and cancer risks before and after diagnosis of rheumatoid arthritis. Arthritis Rheum 62(5):1252–1258PubMedCrossRefGoogle Scholar
  24. 24.
    Bojinca V, Janta I (2012) Rheumatic diseases and malignancies. Maedica 7(4):364–371PubMedCentralPubMedGoogle Scholar
  25. 25.
    Tarella C, Gueli A, Ruella M, Cignetti A (2013) Lymphocyte transformation and autoimmune disorders. Autoimmun Rev 12(8):802–813PubMedCrossRefGoogle Scholar
  26. 26.
    Smedby KE, Baecklund E, Askling J (2006) Malignant lymphomas in autoimmunity and inflammation: a review of risks, risk factors, and lymphoma characteristics. Cancer Epidemiol Biomarkers Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 15(11):2069–2077CrossRefGoogle Scholar
  27. 27.
    Marie I, Guillevin L, Menard JF, Hatron PY, Cherin P, Amoura Z, Cacoub P, Bachelez H, Buzyn A, Le Roux G, Ziza JM, Brice P, Munck JN, Sarrot-Reynauld F, Piette JC, Larroche C (2012) Hematological malignancy associated with polymyositis and dermatomyositis. Autoimmun Rev 11(9):615–620PubMedCrossRefGoogle Scholar
  28. 28.
    Alexson E, Brandt KD (1977) Acute leukemia after azathioprine treatment of connective tissue disease. Am J Med Sci 273(3):335–340PubMedCrossRefGoogle Scholar
  29. 29.
    Kwong YL, Au WY, Liang RH (1998) Acute myeloid leukemia after azathioprine treatment for autoimmune diseases: association with -7/7q. Cancer Genet Cytogenet 104(2):94–97PubMedCrossRefGoogle Scholar
  30. 30.
    Espinosa G, Font J, Munoz-Rodriguez FJ, Cervera R, Ingelmo M (2002) Myelodysplastic and myeloproliferative syndromes associated with giant cell arteritis and polymyalgia rheumatica: a coincidental coexistence or a causal relationship? Clin Rheumatol 21(4):309–313PubMedCrossRefGoogle Scholar
  31. 31.
    Okamoto H, Teramura M, Kamatani N (2004) Myelodysplastic syndrome associated with low-dose methotrexate in rheumatoid arthritis. Ann Pharmacother 38(1):172–173PubMedCrossRefGoogle Scholar
  32. 32.
    Demeter J, Messer G, Ramisch S, Mee JB, di Giovine FS, Schmid M, Herrmann F, Porzsolt F (1996) Polymorphism within the second intron of the IL-1 receptor antagonist gene in patients with hematopoietic malignancies. Cytokines Mol Ther 2(4):239–242PubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2015

Authors and Affiliations

  1. 1.Division of General Internal Medicine, Department of Internal MedicineKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  2. 2.Department of Laboratory MedicineKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  3. 3.Division of Rheumatology, Department of Internal MedicineKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan
  4. 4.Graduate Institute of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  5. 5.Department of Kinesiology, Health and Leisure StudiesNational University of KaohsiungKaohsiungTaiwan
  6. 6.Department of Laboratory Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  7. 7.Graduate Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  8. 8.Department of PediatricsKaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiungTaiwan

Personalised recommendations