Does methotrexate (MTX) increase the risk of developing lymphoma?

From the Guidelines

Methotrexate may slightly increase the risk of developing lymphoma in some patients, but this risk is generally small and must be weighed against the benefits of treatment. Methotrexate is an immunosuppressive medication commonly used to treat autoimmune conditions like rheumatoid arthritis, psoriasis, and inflammatory bowel disease. The increased lymphoma risk appears to be related to both the underlying inflammatory disease activity and the immunosuppressive effects of the medication, as suggested by a multinational evidence-based recommendation study published in the Annals of the Rheumatic Diseases 1. Patients with severe, long-standing inflammatory conditions already have a higher baseline risk of lymphoma, and methotrexate's immunosuppressive properties may potentially allow for abnormal lymphocyte proliferation in some cases. However, it's essential to consider that controlling severe inflammation with methotrexate may actually reduce overall cancer risk in some patients by decreasing chronic inflammation. Some key points to consider include:

• The risk of severe fibrosis and cirrhosis associated with long-term methotrexate use seems low, according to the study 1.
• Methotrexate was not associated with an increased risk of serious infections, including herpes zoster, as reported in the same study 1.
• Five case reports suggest that methotrexate might be associated with Epstein–Barr virus-related lymphoproliferative disease and regression after methotrexate withdrawal, but this evidence is limited and requires further investigation.
• The absolute risk of lymphoma remains quite low, with studies suggesting only a small number of additional lymphoma cases per 10,000 patient-years of treatment. Patients taking methotrexate should have regular follow-up appointments with their healthcare provider to monitor for any concerning symptoms such as persistent swollen lymph nodes, unexplained weight loss, night sweats, or fever.

From the FDA Drug Label

Non-Hodgkin's lymphoma and other tumors have been reported in patients receiving low-dose oral methotrexate However, there have been instances of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment

• Methotrexate (MTX) may increase the risk of developing lymphoma, as there have been reports of Non-Hodgkin's lymphoma in patients receiving low-dose oral MTX.
• The clinical significance of MTX causing chromosomal damage to animal somatic cells and human bone marrow cells remains uncertain.
• Benefits should be weighed against the potential risk before using MTX alone or in combination with other drugs, especially in pediatric patients or young adults 2.

From the Research

Association between Methotrexate and Lymphoma

• Methotrexate (MTX) has been associated with an increased risk of developing lymphoma in patients with rheumatoid arthritis (RA) 3, 4.
• The majority of patients with lymphoproliferation have features of immunosuppression-associated lymphoma, which can be attributed to a combination of factors such as RA itself and the actions of MTX 3, 4.
• Possible oncogenic mechanisms and risk factors for patients with RA to develop lymphoma while receiving MTX include intense immunosuppression, severe disease, genetic predisposition, and an increased frequency of latent infection with prooncogenic viruses like Epstein-Barr virus 3, 4.

Evidence from Studies

• A study published in 1999 found that the spontaneous remission of lymphomas in some patients with RA after MTX was stopped highlights the likely causative role of the drug in the development of these malignancies 3.
• Another study published in 1997 described two cases of lymphoma in patients with RA treated with MTX and reviewed the cases in the world's literature, discussing possible oncogenic mechanisms 4.
• A study published in 2004 found that the overall standardized incidence ratio (SIR) for lymphoma was 1.9, and the SIR for MTX was 1.7, although the confidence intervals for treatment groups overlapped 5.

Risk Factors and Associations

• Lymphoma has been associated with increasing age, male sex, and education 5.
• The use of azathioprine, cyclophosphamide, and MTX has been compared in a matched case-control study, suggesting that RA patients taking azathioprine and MTX may have an increased risk of developing lymphoma, although the results do not necessarily prove this association 6.
• 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 5.