Lymphoma in patients with rheumatoid arthritis: Association with the disease state or methotrexate treatment with the disease state or methotrexate treatment

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Abstract

Although long-term clinical studies have shown no excessive risk of lymphomain rheumatoid arthritis (RA) patients treated with methotrexate (MTX), an increasing number of reports of this association continue to appear. We describe two cases, review the cases in the world's literature, and summarize their important characteristics. Possible oncogenic mechanisms are discussed. Most lymphoproliferation cases presented here have features of immunosuppression-associated lymphoma. The immunosuppressed state is attributable to a combination of factors, such as RA itself and the actions of MTX. The risk factors for RA patients to develop lymphoma while on MTX include severe disease, intense immunosuppression, genetic predisposition, and an increased frequency of latent infection with prooncogenic viruses such as Epstein-Barr virus (EBV). The spontaneous remission of lymphomas in eight RA patients after MTX was stopped highlights the likely causative role of the drug in the development of these malignancies. If the clinical situation permits, a period of observation for spontaneous remission after MTX is stopped is advisable. The physicians caring for RA patients on MTX should maintain a high surveillance for signs and symptoms suggestive of lymphoma.

References (98)

  • MirzaN.M. et al.

    Defective signal transduction via T-cell receptor-CD3 structure in T cells from rheumatoid arthritis patients

    Hum Immunol

    (1993)
  • WangD. et al.

    An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells

    Cell

    (1985)
  • JensenM.K. et al.

    Cytogenetic effect of methotrexate on human cells in vivo: comparison between results obtained by chromosome studies on bone marrow cells and bloodlymphocytes and by the micronucleus test

    Mutat Res

    (1979)
  • LindskovR. et al.

    Sister chromatid exchange in patients treated with methotrexate for psoriasis

    J Invest Dermatol

    (1984)
  • MeliefC.J.M.

    Tumor eradication by adoptive transfer of cytotoxic T lymphocytes

    Adv Cancer Res

    (1992)
  • BowlinT.L. et al.

    Methylacetylenic putrescine (MAP) an inhibitor of polyamine biosynthesis reduces the frequency and cytolytic activity of alloantigen-induced lyt 2.2 positive lymphocytes in vivo

    Int J Immunopharmacol

    (1989)
  • BowlinT.L. et al.

    Intracellular polyamine biosynthesis is required for interleukin 2 responsiveness during lymphocyte mitogenesis

    Cell Immunol

    (1987)
  • O'MearaA. et al.

    Effect of methotrexate on the immune responses in children with acute lymphatic leukemia

    Immunopharmacology

    (1985)
  • BoerboomsA.M.T. et al.

    Infections during low-dose methotrexate treatment in rheumatoid arthritis

    Semin Arthritis Rheum

    (1995)
  • RustiaM. et al.

    Life-span carcinogenicity tests with 4-amino-N10-methylpteroylglutamic acid (methotrexate) in Swiss mice and Syrian golden hamsters

    Toxicol Appl Pharmacol

    (1973)
  • Annual prescriptions for methotrexate number approximately1.25 million, with an estimated 50-60 percent of these for...
  • WeinblattM.E. et al.

    Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis: 84-month update

    Arthritis Rheum

    (1992)
  • KremerJ.M. et al.

    Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis: update after a mean of 90 months

    Arthritis Rheum

    (1992)
  • FurstD.E. et al.

    Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis

    J Rheumatol

    (1990)
  • TishlerM. et al.

    Long-term experience with low dose methotrexate in rheumatoid arthritis

    Rheumatol Int

    (1993)
  • RustinG.H.S. et al.

    No increase in second tumors after cytotoxic chemotherapy for gestational trophoblastic tumors

    N Engl J Med

    (1983)
  • BailinP.L. et al.

    Is methotrexate therapy for psoriasis carcinogenic?

    JAMA

    (1975)
  • SternR.S. et al.

    Methotrexate used for psoriasis and the risk of noncutaneous or cutaneous malignancy

    Cancer

    (1982)
  • NyforsA. et al.

    Frequency of malignant neoplasm in 248 long-term methotrexate treated psoriatics

    Dermatologica

    (1983)
  • CarmeliY. et al.

    Regression of Kaposi's sarcoma after intravenous immunoglobulin treatment for polymyositis

    Cancer

    (1994)
  • HarrisonP.V. et al.

    Methotrexate, psoriasis, and malignancy

    Lancet

    (1984)
  • BolognaC. et al.

    Study of 8 cases of cancer observed in 458 rheumatoid arthritis (RA) patients treated with methotrexate (MTX)

    Arthritis Rheum

    (1995)
  • SanyJ. et al.

    Treatment of rheumatoid arthritis with methotrexate: a prospective open longterm study of 191 cases

    J Rheumatol

    (1991)
  • ShirokyJ.B. et al.

    Complications of immunosuppression associated with weekly low dose methotrexate

    J Rheumatol

    (1991)
  • EllmanM.H. et al.

    Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate

    J Rheumatol

    (1991)
  • KingsmoreS.F. et al.

    Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review

    J Rheumatol

    (1992)
  • TaillanB. et al.

    Lymphoma developing in a patient with rheumatoid arthritis taking methotrexate

    Clin Rheum

    (1993)
  • KamelO.W. et al.

    Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis

    N Engl J Med

    (1993)
  • Cobeta-GarciaJ.C. et al.

    Non-Hodgkin's lymphoma, rheumatoid arthritis and methotrexate (letter)

    J Rhematol

    (1993)
  • MorrisC.R. et al.

    Localized lymphoma in a patient with rheumatoid arthritis treated with parenteral methotrexate (letter)

    J Rheumatol

    (1993)
  • Le GoffP. et al.

    Lymphoma in a patient under low-dose methotrexate for rheumatoid arthritis: a new case (letter)

    Rev Rhum Mal Osteoartic

    (1994)
  • LiotéF. et al.

    Methotrexate related B lymphoproliferative disease in a patient with rheumatoid arthritis: role of Epstein-Barr virus infection

    J Rheumatol

    (1995)
  • DaviesJ.M.S. et al.

    Lymphomatous changes during methotrexate therapy [abstract]

    Arthritis Rheum

    (1995)
  • BachmanT.R. et al.

    Methotrexate associated lymphoma in patients with rheumatoid arthritis: report of two cases

    Arthritis Rheum

    (1996)
  • van de RijnM. et al.

    Epstein-Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis

    Arthritis Rheum

    (1996)
  • ModerK.G. et al.

    Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study

    Am J Med

    (1995)
  • WilliamsC.A. et al.

    Lymphoma and leukemia in rheumatoid arthritis: a matched case-control study in the ARAMIS (arthritis, rheumatism and aging medical information system) population

    Arthritis Rheum

    (1995)
  • ShirokyJ.B. et al.

    Reversible lymphomas

    N Engl J Med

    (1993)
  • PennI.

    Why do immunosuppressed patients develop cancer?

    Crit Rev Oncog (United States)

    (1989)
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