Does Rheumatoid Arthritis Drug Increase Cancer Risk?

New research challenges reports of methotrexate danger

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Methotrexate is an immune suppressive drug used to treat certain types of cancer as well as a number of autoimmune disorders, including severe psoriasis and rheumatoid arthritis (RA).

Ironically, a number ​of studies have suggested that methotrexate may, in fact, increase the risk of cancer in people with RA, including melanoma, leukemia, myeloma, lung cancer, and lymphoma.

In the 10 years since the first of these studies was published, there has been ongoing debate as to how real the risk may be. Is methotrexate safe to use, or are there factors that may place some individuals at greater risk than others?

What the Early Research Told Us

In 2008, an Australian study reviewed the medical histories of 309 women and 150 men with RA who had used methotrexate before 1986 and comparing the rate of cancer in that group to that of the general population.

According to research, people with RA who had been exposed to methotrexate had a 50 percent greater risk of developing cancers of any type. Moreover, they had a five-fold increase in the risk of non-Hodgkin lymphoma (NHL) as well as a three-fold increase in lung cancer and melanoma risk.

Out of the 459 people included in the study, 87 malignancies were identified.

While the study supported earlier research into the risk of NHL and lung cancer in people on methotrexate-based therapy, many in the scientific community remained unclear as to whether methotrexate was the culprit or the disease itself.

This was especially true for melanoma since the design of the study didn't allow for the inclusion of such risk factors as age or sun exposure.

What the Recent Research Tells Us

In 2017, scientists at the University of Gothenburg in Sweden conducted a retrospective study to look specifically at the risk of melanoma in methotrexate-treated patients with RA.

Using statistics from the National Board of Health and Welfare, the investigators reviewed the case files of anyone over the age of 18 who has been dispensed the drug from 2005 to 2014.

According to the published study, people with RA who had been treated with methotrexate only had a 10 percent greater risk of melanoma than the general population. Moreover, the bulk of these cases involved women who had started treatment after the age of 70. As such, age may play a far bigger role given that melanomas are typically seen in people over 65.

Other researchers, meanwhile, have begun to investigate the association between RA and cancer irrespective of methotrexate. One such investigation conducted by the University of Maryland School of Medicine reviewed data from seven high-quality clinical studies published between 2008 and 2014.

A total of nine publications met the inclusion criteria. Seven investigated the overall risk of cancer in people with RA; eight looked at lymphoma, melanoma, lung, colorectal, and breast cancer; seven focused on prostate cancer, and four conducted investigations into cervical cancer.

Upon completion of the review, the researchers reported that the overall risk of cancer was only around 10 percent greater than the general population. Moreover, the risk of breast, cervical, colorectal, and prostate cancer was actually lower by comparison.

The same did not hold true for other cancers. Among the findings:

  • The rate of lymphoma was exceptionally high, especially Hodgkin disease which had a 12-fold increase in risk.
  • Lung cancer generally showed a twofold increase.
  • Melanoma had a slightly less than 25 percent increase

Not surprisingly, these were cancers specifically highlighted in the Australian study.

This doesn't suggest that methotrexate played no part in the cancer risk. It simply tells us that extra care needs to be taken to ensure cancer screening in people with RA whether methotrexate is prescribed or not.

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  • Buchbinder, R.; Barber, M.; Heuzenroeder, L. et al. "Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate." Arthritis Rheum. 2008;59(6): 794-9. DOI: 10.1002/art.23716.
  • Polesie, S.; Gillstedt, M.; Son, H. et al. "Methotrexate treatment and risk for cutaneous malignant melanoma: a retrospective comparative registry-based cohort study." Brit J Derma. 2017; 176 (6);1492-1499. DOI: 10.1111/bjd.15170.
  • Simon, T.; Thompson, A.; Gandhi, K. et al. "Incidence of malignancy in adult patients with rheumatoid arthritis: a .meta-analysis." .Arthritis Res Ther. 2015; 17(1):212. DOI: 10.1186/s13075-015-0728-9.