Risk of lymphoma in patients receiving antitumor necrosis factor therapy: a meta-analysis of published randomized controlled studies

Clin Rheumatol. 2012 Apr;31(4):631-6. doi: 10.1007/s10067-011-1895-y. Epub 2011 Nov 18.


The 2008 edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid tissues recognizes a new diagnostic entity termed "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" highlighting lymphomas arising in patients treated with immunosuppressive agents for autoimmune disorders. The role of antitumor necrosis factor alpha therapy (anti-TNFα) and lymphoma risk in rheumatoid arthritis (RA) patients remains unclear; therefore, the goal of our study was to determine whether anti-TNFα therapy is associated with iatrogenic lymphomas. A meta-analysis of all randomized controlled clinical trials published (2000-2009) in RA patients receiving anti-TNFα therapy was performed. Fourteen studies fulfilled all search criteria and included 2,306 control patients and 5,179 patients treated with anti-TNFα therapy, namely etanercept, adalumimab, and infliximab. Clinical information including the number of patients, age, gender, lymphoma rates, and follow-up time was recorded. The overall rate and rate differences were analyzed using the DerSimonian and Laird method. Of the control group, four (4/2,306, 0.17%) patients developed hematolymphoid neoplasms. Eleven (11/5,179, 0.21%) patients receiving anti-TNFα therapy developed lymphomas. The adjusted overall rates are 0.36 lymphomas per 1,000 person-years in patients who did not receive anti-TNFα therapy versus 1.65 lymphomas per 1,000 person-years in patients who received anti-TNFα therapy. The corresponding 95% confidence interval for this rate difference is (-0.214, 2.79). The adjusted rate difference is 1.29 lymphomas per 1,000 person-years (95% CI, -0.21, 2.8; p value = 0.093). The corresponding p value is p = 0.0928. There is a suggestion of increased lymphomas in the treated group, with the predominant subset being B-cell lymphomas. Since the outcome of lymphoma is rare, it does not reach statistical significance of p < 0.05.

Publication types

  • Meta-Analysis

MeSH terms

  • Adalimumab
  • Antibodies, Monoclonal / adverse effects*
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy*
  • Etanercept
  • Humans
  • Immunoglobulin G / adverse effects*
  • Infliximab
  • Lymphoma / epidemiology*
  • Randomized Controlled Trials as Topic
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


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