Rheumatoid arthritis and lymphoma

by Nathan Wei, MD, FACP, FACR

Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.

Click here: Second Opinion Arthritis Treatment Kit

Whether lymphoma risk is linked to rheumatoid arthritis alone or to the drugs used to treat it is a hot topic for debate.

Severe and longstanding rheumatoid arthritis leads to 70 times the risk for developing lymphoma compared with patients having mild disease.

Aggressive treatment of RA may reduce patients' risk of lymphoma by reducing cumulative inflammation, reported Eva Baecklund, M.D., of the Akademiska Hospital and colleagues in a study published in the March 2006 issue of Arthritis & Rheumatism.

The good news is that standard disease-modifying, anti-rheumatic drug (DMARD) treatment was not associated with increased lymphoma risk, the researchers concluded.

Drawing from a national register of nearly 75,000 Swedish RA patients, the study focused on 378 of them who were diagnosed with malignant lymphoma between 1964 and 1995. Using 378 individually matched RA patients who were free of lymphoma, the researchers calculated odds ratios for lymphoma associated with low, medium, and high RA disease activity.

Compared with patients with low disease activity, those with medium disease activity had a more than sevenfold increase in lymphoma risk (odds ratio=7.7; 95% confidence interval=4.8-12.3), and those with high disease activity had a 71-fold risk increase (OR=71.3; 95% CI=24.1-211.4).

Fifty-two percent of RA patients with lymphoma were categorized with medium disease, and 23% of RA patients were classified as having high disease activity, based on duration of symptoms and swollen and tender joint counts.

The researchers also looked for an association between lymphoma risk and RA treatment, including methotrexate, anti-malarial agents, oral steroids, non-steroidal anti-inflammatory drugs, and aspirin. But no link association was found.

Only the drug azathioprine (Imuran, Azasan) was associated with significantly increased lymphoma risk (OR=4.3; 95% CI=1.6-12.0), but this drug is not regarded as a traditional DMARD and is rarely used in current RA treatment.

The chronic inflammation and stimulation of the immune system in RA likely leads to cancer through as-yet unspecified pathways, the researchers speculated.

"The association between lymphoma risk and very high and/or longstanding disease activity indicates that most patients with RA will never have any clinically relevant increased lymphoma risk," the authors said. "In contrast, those who do may have highly increased risks, but can be readily identified based on their accrued inflammatory burden."

They added, "Conventional medical treatment to suppress and alleviate disease activity is not by itself a risk factor for lymphoma. Rather, it is possible that aggressive treatment may reduce lymphoma risk by reducing cumulative inflammation."

[Baecklund E et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis & Rheumatism. 2006; 54(3):692-701.]

Recent case reports suggest a possible association between MTX and lymphoma.

Drug Saf. 1999 Jun;20(6):475-87.

Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate?

Georgescu L, Paget SA.

The New York Hospital, Cornell University Medical Center, New York 10021, USA. GEORGESCUL@HSS.edu

An increasing number of instances of lymphoma in patients with rheumatoid arthritis who are treated with methotrexate continue to appear. The majority of patients with lymphoproliferation have features of immunosuppression-associated lymphoma. Rheumatoid arthritis itself and the actions of methotrexate concur in leading to a immunosuppressed state. Possible oncogenic mechanisms and the risk factors for patients with rheumatoid arthritis to develop lymphoma while receiving methotrexate include: (i) intense immunosuppression and severe disease in combination with genetic predisposition and; (ii) an increased frequency of latent infection with prooncogenic viruses like Epstein-Barr virus. The aetiological role of methotrexate in the development of these lymphomas is supported by the spontaneous remission of these malignancies in some of patients with rheumatoid arthritis after methotrexate has been stopped. The physicians caring for patients with rheumatoid arthritis receiving methotrexate should be vigilant about signs and symptoms suggestive of lymphoma, mostly in those patients with significant comorbidity, long standing and severe disease who are more likely to be immunosuppressed. If a lymphoma appears in these patients, methotrexate should be stopped. Spontaneous remission may occur and a period of observation is advisable when clinically possible. If functional deterioration appears or there are signs of lymphoproliferative organ invasion after several months then specific antineoplastic treatment should be instituted.

Other studies suggesting a link are:

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

Kamel OW, van de Rijn M, Weiss LM, Del Zoppo GJ, Hench PK, Robbins BA, Montgomery PG, Warnke RA, Dorfman RF: Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1317-1321, 1993

Kingsmore SF, Hall BD, Allen NB, Rice JR, Caldwell DS: Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review. J Rheumatol 19:1462-1465, 1992

However, a large retrospective study of 16,263 patients with RA showed no increased risk (Moder KG, Tefferi A, Cohen MD, Menke DM, Luthra HS: Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study. Am J Med 99:276-281, 1995). In that study, only 12 of 39 patients who developed lymphoma were treated with MTX, and of those, there was no relationship with cumulative dose or duration of treatment. More studies are required; nevertheless, patients should be advised to report any lymph node swelling, and the lymph nodes should be routinely examined by the treating physician.

On the other hand, some studies have shown that when rheumatoid arthritis patients quit taking methotrexate, their lymphoma went into regression, a possible sign that the drug directly contributes to the cancer. Some studies have indicated that the drug's immune-weakening effect places people at risk for viral-associated lymphomas.

Another factor in this story: Epstein-Barr virus (EBV), a herpes virus that is common among adults. Some 90% of adults are said to have EBV, which is associated with mononucleosis and other infections -- but in the vast majority of people, the virus remains latent, never causing an infection. EBV has also been linked with lymphoma.

In one study, methotrexate was shown to activate latent EBV in cells infected with the virus. High levels of circulating infectious particles of the EBV were also found in patients taking methotrexate for rheumatoid arthritis compared with patients taking other immune-weakening drugs.

A recent study published by a Swedish group in the British Medical Journal suggested that anti-TNF drugs were not associated a3with an increased risk of lymphoma.. The articles conclusion, “Overall, RA-patients are at equally elevated risks for lymphomas and leukemias. RA-patients treated with TNF-antagonists did not have higher lymphoma risks than other RA-patients. Prolonged observation is needed to determine the long-term effects of TNF-antagonists on lymphoma risk.”

(Askling J, et al, Hematopoietic malignancies in rheumatoid arthritis. Lymphoma risk and characteristics following TNF- antagonists)

Bottom line: The jury is still out regarding whether the medicines that are used to treat RA confer any greater risk of lymphoma than the disease itself.

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