Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients

Arthritis Rheum. 2004 Jun;50(6):1740-51. doi: 10.1002/art.20311.


Objective: The risk of lymphoma is increased in patients with rheumatoid arthritis (RA), and spontaneous reporting suggests that methotrexate (MTX) and anti-tumor necrosis factor (anti-TNF) therapy might be associated independently with an increased risk of lymphoma. However, data from clinical trials and clinical practice do not provide sufficient evidence concerning these issues because of small sample sizes and selected study populations. The objective of this study was to determine the rate of and standardized incidence ratio (SIR) for lymphoma in patients with RA and in RA patient subsets by treatment group. Additionally, we sought to determine predictors of lymphoma in RA.

Methods: We prospectively studied 18,572 patients with RA who were enrolled in the National Data Bank for Rheumatic Diseases (NDB). Patients were surveyed biannually, and potential lymphoma cases received detailed followup. The SEER (Survey, Epidemiology, and End Results) cancer data resource was used to derive the expected number of cases of lymphoma in a cohort that was comparable in age and sex with the RA cohort.

Results: The overall SIR for lymphoma was 1.9 (95% confidence interval [95% CI] 1.3-2.7). The SIR for biologic use was 2.9 (95% CI 1.7-4.9) and for the use of infliximab (with or without etanercept) was 2.6 (95% CI 1.4-4.5). For etanercept, with or without infliximab, the SIR was 3.8 (95% CI 1.9-7.5). The SIR for MTX was 1.7 (95% CI 0.9-3.2), and was 1.0 (95% CI 0.4-2.5) for those not receiving MTX or biologics. Lymphoma was associated with increasing age, male sex, and education.

Conclusion: Lymphomas are increased in RA. Although the SIR is greatest for anti-TNF therapies, differences between therapies are slight, and confidence intervals for treatment groups overlap. The increased lymphoma rates observed with anti-TNF therapy may reflect channeling bias, whereby patients with the highest risk of lymphoma preferentially receive anti-TNF therapy. Current data are insufficient to establish a causal relationship between RA treatments and the development of lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal / adverse effects
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / epidemiology*
  • Databases, Factual
  • Etanercept
  • Female
  • Follow-Up Studies
  • Humans
  • Immunoglobulin G / adverse effects
  • Incidence
  • Infliximab
  • Lymphoma, Non-Hodgkin / epidemiology*
  • Lymphoma, Non-Hodgkin / etiology
  • Male
  • Methotrexate / adverse effects*
  • Middle Aged
  • Prospective Studies
  • Receptors, Tumor Necrosis Factor
  • Risk Factors
  • SEER Program
  • Severity of Illness Index
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Antibodies, Monoclonal
  • Antirheumatic Agents
  • Immunoglobulin G
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Infliximab
  • Etanercept
  • Methotrexate