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Influence of methotrexate, leflunomide and tumour necrosis factor alpha inhibitors on immune competence in rheumatoid arthritis patients: a long-run monitoring of Epstein–Barr virus load

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The risk to develop lymphoma is doubled in patients with rheumatoid arthritis (RA) in the absence of immunosuppressive therapy. This risk is slightly increased by the use of methotrexate or tumour necrosis factor alpha inhibitors (infliximab and etanercept) [1]. Epstein–Barr virus (EBV) is detected in about one-third of lymphoma developing in RA patients. The reason why some patients develop lymphoma is unknown. We have previously shown that RA patients have an almost 10-fold increase of EBV load in their peripheral blood mononuclear cells (PBMCs), compared with normal controls [2]. RA patients' peripheral blood EBV load is similar to that of healthy transplant recipients (10 copies per 500 ng DNA). In immunosuppressed transplant recipients, elevation of PBMC EBV load above 500 copies/500 ng DNA predicts the emergence of lymphoma.


We followed RA patients to evaluate the effects of disease-modifying anti-rheumatic drugs (DMARDs) (methotrexate and leflunomide) and tumour necrosis factor alpha inhibitors (infliximab and etanercept) on PBMC EBV load and to predict lymphoma development.


One hundred and nineteen patients fulfilling the 1987 ACR criteria for RA were followed for periods of 6 months–4 years. Twenty patients received methotrexate or leflunomide, eight received only infliximab, 61 received methotrexate and infliximab, and 30 received etanercept. A 214 bp fragment from the conserved long Internal Repeat IR1 was amplified by quantitative PCR to evaluate EBV DNA load. Effect of treatment duration on EBV load was analyzed by the method of generalized estimation equations.


EBV load decreased between the beginning and the end of the study in patients receiving DMARDs (mean: 20.24 and 3.27) or etanercept (mean: 4.44 and 0.67). This decrease was significant for DMARDs (P = 0.0038). However, EBV load evolution was not significantly related to treatment duration in patients under infliximab (mean: 6.36 and 7.82) or infliximab plus methotrexate (mean: 13.49 and 11.92). Of interest, in one patient receiving infliximab plus methotrexate, EBV load reached 540 copies/500 ng over a short period of time.


Methotrexate and etanercept decrease EBV load over time. Infliximab alone or with methotrexate does not influence significantly EBV load. Monitoring EBV load might help detecting the few patients who are likely to develop lymphoma.


  1. 1.

    Wolfe F, Michaud K: Lymphoma in rheumatoid arthritis. The effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum. 2004, 50: 1740-1751. 10.1002/art.20311.

  2. 2.

    Balandraud N, Meynard JB, Auger I, Sovran H, Mugnier B, Reviron D, Roudier J, Roudier C: Epstein–Barr virus load in the peripheral blood of patients with rheumatoid arthritis. Accurate quantification using real-time polymerase chain reaction. Arthritis Rheum. 2003, 48: 1223-1228. 10.1002/art.10933.

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Supported by PHRC 2003, SFR and ARP.

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  • Lymphoma
  • Methotrexate
  • Infliximab
  • Rheumatoid Arthritis Patient
  • Transplant Recipient