Skip to main content

Advertisement

SpringerLink
Log in

Characteristics and risk factors of lymphoproliferative disorders among patients with rheumatoid arthritis concurrently treated with methotrexate: a nested case-control study of the IORRA cohort

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

Abstract

The purpose of the study is to demonstrate the characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA) and risk factors for LPD among RA patients concurrently treated with methotrexate (MTX). Among patients who participated in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study in October 2010, past existence of LPD from patient’s report was confirmed through medical charts. Background factors, LPD pathological findings, and the clinical courses of LPD and RA after LPD were assessed. To analyze the risk of MTX-associated LPD among RA patients concurrently treated with MTX, a nested case-control study design was used to select control patients who had received MTX but did not develop LPD by matching calendar date, sex, and age (within 5 years) at a 1:10 ratio. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for occurrence of LPD were analyzed by multivariate analysis. Forty-eight patients experienced LPD among 5757 patients, and 25 (52.1%) of those had lymphoma. LPD regressed in 60.4% of all LPD patients and 24.0% of lymphoma patients. In the 26 cases who developed LPD during MTX treatment, multivariate analysis revealed that 28-joint disease activity score (DAS28) (OR 1.57 [95% CI, 1.12–1.57]; p < 0.01) and lactate dehydrogenase (LDH) level (OR 1.01 [95% CI, 1.00–1.02]; p < 0.01), but not concomitant dose of MTX, were risk factors for LPD. Among RA patients concomitantly treated with MTX, high disease activity, but not MTX dose, was a risk factor for the occurrence of LPD.

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

Similar content being viewed by others

References

  1. Radner H, Smolen JS, Aletaha D (2011) Comorbidity affects all domains of physical function and quality of life in patients with rheumatoid arthritis. Rheumatology (Oxford) 50:381–388

    Article  Google Scholar 

  2. Nakajima A, Inoue E, Shimizu Y et al (2015) Presence of comorbidity affects both treatment strategies and outcomes in disease activity, physical function, and quality of life in patients with rheumatoid arthritis. Clin Rheumatol 34:441–449

    Article  PubMed  Google Scholar 

  3. Sokka T, Abelson B, Pincus T (2008) Mortality in rheumatoid arthritis: 2008 update. Clin Exp Rheumatol 26:S35–S61

    CAS  PubMed  Google Scholar 

  4. Nakajima A, Inoue E, Tanaka E et al (2010) Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA. Scand J Rheumatol 39:360–367

    Article  CAS  PubMed  Google Scholar 

  5. Prior P, Symmons DP, Hawkins CF, Scott DL, Brown R (1984) Cancer morbidity in rheumatoid arthritis. Ann Rheum Dis 43:128–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mariette X, Tubach F, Bagheri H et al (2010) Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis 69:400–408

    Article  CAS  PubMed  Google Scholar 

  7. Yamada T, Nakajima A, Inoue E et al (2011) Incidence of malignancy in Japanese patients with rheumatoid arthritis. Rheumatol Int 31:1487–1492

    Article  PubMed  Google Scholar 

  8. 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 317:180–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ellman MH, Hurwitz H, Thomas C, Kozloff M (1991) Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. J Rheumatol 18:1741–1743

    CAS  PubMed  Google Scholar 

  10. Gaulard P, Swerdlow S, Harris N, Jaffe E, Sundstrom C (2008) Other iatrogenic immunodeficiency-associated lymphoproliferative disorders. In: Swerdlow S, Campo E, Harris N et al (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tssues, 4th edn. IARC Press, Lyon, pp 350–351

    Google Scholar 

  11. Salloum E, Cooper DL, Howe G et al (1996) Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 14:1943–1949

    Article  CAS  PubMed  Google Scholar 

  12. Baird RD, van Zyl-Smit RN, Dilke T, Scott SE, Rassam SM (2002) Spontaneous remission of low-grade B-cell non-Hodgkin’s lymphoma following withdrawal of methotrexate in a patient with rheumatoid arthritis: case report and review of the literature. Br J Haematol 118:567–568

    Article  PubMed  Google Scholar 

  13. Baecklund E, Iliadou A, Askling J et al (2006) Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 54:692–701

    Article  PubMed  Google Scholar 

  14. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA et al (2012) Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 308:898–908

    Article  CAS  PubMed  Google Scholar 

  15. Askling J, Fored CM, Baecklund E et al (2005) Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis 64:1414–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen Y, Sun J, Yang Y, Huang Y, Liu G (2016) Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses. Clin Rheumatol 35:1–18

    Article  CAS  PubMed  Google Scholar 

  17. Hoshida Y, Xu JX, Fujita S et al (2007) Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication. J Rheumatol 34:322–331

    CAS  PubMed  Google Scholar 

  18. Takemori N, Kaneko H, Nakamura M, Kojima M (2012) Complete remission of methotrexate-related Epstein-Barr-virus-associated Hodgkin-like lymphoma following withdrawal of MTX coupled with clarithromycin administration. Case Rep Hematol 2012:658745

    PubMed  PubMed Central  Google Scholar 

  19. Kawano N, Ono N, Yoshida S et al (2012) Successful treatment of immunodeficiency-associated EBV-negative lymphoproliferative disorders in rheumatoid arthritis by methotrexate withdrawal and prevention of its relapse by rituximab administration. J Clin Exp Hematop 52:193–198

    Article  PubMed  Google Scholar 

  20. Yoshida Y, Takahashi Y, Yamashita H, Kano T, Kaneko H, Mimori A (2014) Clinical characteristics and incidence of methotrexate-related lymphoproliferative disorders of patients with rheumatoid arthritis. Mod Rheumatol 24:763–765

    Article  CAS  PubMed  Google Scholar 

  21. Rizzi R, Curci P, Delia M et al (2009) Spontaneous remission of “methotrexate-associated lymphoproliferative disorders” after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature. Med Oncol 26:1–9

    Article  CAS  PubMed  Google Scholar 

  22. Singh JA, Furst DE, Bharat A et al (2012) 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 64:625–639

    Article  CAS  Google Scholar 

  23. Yamanaka H, Inoue E, Tanaka E et al (2007) Influence of methotrexate dose on its efficacy and safety in rheumatoid arthritis patients: evidence based on the variety of prescribing approaches among practicing Japanese rheumatologists in a single institute-based large observational cohort (IORRA). Mod Rheumatol 17:98–105

    Article  CAS  PubMed  Google Scholar 

  24. Nakajima A, Inoue E, Shidara K et al (2011) Standard treatment in daily clinical practice for early rheumatoid arthritis improved disease activity from 2001 to 2006. Mod Rheumatol 21:594–597

    Article  PubMed  Google Scholar 

  25. Matsuda Y, Singh G, Yamanaka H et al (2003) Validation of a Japanese version of the Stanford Health Assessment Questionnaire in 3,763 patients with rheumatoid arthritis. Arthritis Rheum 49:784–788

    Article  PubMed  Google Scholar 

  26. Chiesa Fuxench ZC, Shin DB, Ogdie Beatty A, Gelfand JM (2016) The risk of cancer in patients with psoriasis: a population-based cohort study in the Health improvement network. JAMA Dermatol 152:282–290

    Article  PubMed  PubMed Central  Google Scholar 

  27. Vockerodt M, Yap LF, Shannon-Lowe C et al (2015) The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol 235:312–322

    Article  PubMed  Google Scholar 

  28. Petrara MR, Giunco S, Serraino D, Dolcetti R, De Rossi A (2015) Post-transplant lymphoproliferative disorders: from epidemiology to pathogenesis-driven treatment. Cancer Lett 369:37–44

    Article  CAS  PubMed  Google Scholar 

  29. Kondo S, Tanimoto K, Yamada K et al (2013) Mature T/NK-cell lymphoproliferative disease and Epstein-Barr virus infection are more frequent in patients with rheumatoid arthritis treated with methotrexate. Virchows Arch 462:399–407

    Article  CAS  PubMed  Google Scholar 

  30. Komatsuda A, Wakui H, Nimura T, Sawada K (2008) Reversible infliximab-related lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis. Mod Rheumatol 18:315–318

    Article  CAS  PubMed  Google Scholar 

  31. Mo N, Muthu S, O’Sullivan M (2011) Regression of lymphoma after withdrawal of infliximab alone in an infliximab/methotrexate-treated RA patient. Rheumatology (Oxford) 50:808–810

    Article  Google Scholar 

  32. Smolen JS, Landewe R, Breedveld FC et al (2014) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 73:492–509

    Article  CAS  PubMed  Google Scholar 

  33. Singh JA, Saag KG, Bridges SL Jr et al (2016) 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 68:1–25

    Article  Google Scholar 

  34. Bombardier C, Hazlewood GS, Akhavan P et al (2012) Canadian Rheumatology association recommendations for the pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs: part II safety. J Rheumatol 39:1583–1602

    Article  CAS  PubMed  Google Scholar 

  35. Strangfeld A, Hierse F, Rau R et al (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  PubMed Central  Google Scholar 

  36. Dixon WG, Watson KD, Lunt M et al (2010) Influence of anti-tumor necrosis factor therapy on cancer incidence in patients with rheumatoid arthritis who have had a prior malignancy: results from the British Society for Rheumatology Biologics Register. Arthritis Care Res (Hoboken) 62:755–763

    Article  CAS  Google Scholar 

  37. Silva-Fernandez L, Lunt M, Kearsley-Fleet L et al (2016) The incidence of cancer in patients with rheumatoid arthritis and a prior malignancy who receive TNF inhibitors or rituximab: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis. Rheumatology (Oxford) 55:2033–2039

    Article  Google Scholar 

  38. Tokuhira M, Watanabe R, Nemoto T et al (2012) Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis. Leuk Lymphoma 53:616–623

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The IORRA study was organized and supported by the Tokyo Women’s Medical University. We thank all of the rheumatologists at the Institute of Rheumatology, Tokyo Women’s Medical University for participating in the IORRA study.

Author information

Authors and Affiliations

  1. Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo, 162-0054, Japan

    Yoko Shimizu, Ayako Nakajima, Eisuke Inoue, Kumi Shidara, Naoki Sugimoto, Yohei Seto, Eiichi Tanaka, Shigeki Momohara, Atsuo Taniguchi & Hisashi Yamanaka

Authors
  1. Yoko Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayako Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eisuke Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kumi Shidara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoki Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yohei Seto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eiichi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shigeki Momohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Atsuo Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hisashi Yamanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayako Nakajima.

Ethics declarations

Conflict of interest

This study is currently being executed independently from companies. We declare the received honoraria for lectures or consultancies from the following companies: Y. Shimizu, none; A. Nakajima, none; E. Inoue, none; K. Shidara, none; N. Sugimoto, none; Y. Seto, none; E. Tanaka, none; S. Momohara, none, A. Taniguchi, none; H. Yamanaka, AbbVie, Astellas Pharma Inc., Chugai Pharmaceutical Co., Bristol-Meyers Squibb K.K., Daiichi-Sankyo Co., Ltd., Mitsubishi-Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd., and UCB Japan Co., Ltd.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shimizu, Y., Nakajima, A., Inoue, E. et al. Characteristics and risk factors of lymphoproliferative disorders among patients with rheumatoid arthritis concurrently treated with methotrexate: a nested case-control study of the IORRA cohort. Clin Rheumatol 36, 1237–1245 (2017). https://doi.org/10.1007/s10067-017-3634-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-017-3634-5

Keywords

Search

Navigation