Is Cancer Risk Higher in People With Rheumatoid Arthritis?

Do Treatment Choices Affect Cancer Risk?

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When considering cancer risk in people with rheumatoid arthritis, it is helpful to consider specific types of cancer separately. While the overall cancer risk in people with rheumatoid arthritis is considered comparable to the general population, there is a slightly higher incidence of lymphoma and lung tumors and a lower incidence of colorectal and breast tumors in those with rheumatoid arthritis.

Biologic Drugs and Cancer Risk

Since biologic drugs were developed and marketed for the treatment of rheumatoid arthritis starting  in 1998, concerns about cancer risk have grown. Not only are there questions about the risk of cancer in people with rheumatoid arthritis, there are questions regarding rheumatoid arthritis treatment. Prior to the availability of biologics drugs, specifically TNF inhibitors, traditional DMARDs (disease-modifying anti-rheumatic drugs) were used to treat rheumatoid arthritis. Traditional DMARDs include methotrexate, sulfasalazine, hydroxychloroquine, and gold salts. While there are adverse events associated with all of these drugs, concern escalated over the risk of serious infections and malignancy after TNF inhibitors were introduced.

TNF (tumor necrosis factor) is a proinflammatory cytokine. But, it is the other role which TNF plays in the body, to promote tumor cell necrosis and death, that raised concern about a potential link to malignancy.

In other words, if we inhibit TNF for the purpose of controlling inflammation, are we allowing cancer to develop? Based on a few post-market reports of lymphoma in patients treated with TNF inhibitors for rheumatoid arthritis, the FDA added a warning about the potential risk for malignancy to the label of TNF inhibitors in March 2003.

Since that time, observational studies, meta-analyses, and retrospective analysis have allowed us to take a closer look at the overall risk of cancer in adults with rheumatoid arthritis, the risk of specific cancers, as well as whether the type of TNF inhibitor makes a difference or how long the TNF inhibitor is used.

Study Results

Only one published meta-analysis study (Bongartz et al., 2006) has shown an increased risk of cancer in rheumatoid arthritis patients treated with TNF inhibitors versus placebo. This study involved over 5,000 rheumatoid arthritis patients from 9 randomized, controlled trials that lasted from 3 to 12 months. There was found to be a statistically significant risk of malignancy among patients treated with Humira (adalimumab) or Remicade (infliximab) compared to placebo.

But, several other meta-analysis studies, including Mariette et al. (2011), Askling et al. (2011), and Wolfe and Michaud (2007), did not find a similar risk of overall malignancy in rheumatoid arthritis patients treated with TNF inhibitors.

Specific Types of Cancer

Lymphoma - It is known that people with rheumatoid arthritis have about twice the risk of developing lymphoma compared to the general population.

Disease activity and severity may hike the risk even more. The only large, observational study that compared rheumatoid arthritis patients treated with a TNF inhibitor to those on traditional (non-biologic) DMARDs showed no increased lymphoma risk (Wolfe and Michaud 2007b).

Skin Cancer - Based on a number of studies, there may be a small increased risk of skin cancer associated with the use of TNF inhibitors to treat rheumatoid arthritis. There have been positive and negative studies associated with melanoma and non-melanoma skin cancer.

Lung Cancer - Based on an analysis of 12 studies, people with rheumatoid arthritis have an increased risk of developing lung cancer compared to the general population.

People with rheumatoid arthritis are 63% more likely than the general population to develop lung cancer, according to Johns Hopkins.

Breast Cancer - A systematic literature search of randomized, controlled trials from January 1998 to July 2013 compared rheumatoid arthritis patients treated with one of 5 TNF inhibitors to placebo, methotrexate, TNF inhibitor plus methotrexate, or placebo plus methotrexate for more than 24 weeks. Study results did not find a statistically significant increase in breast cancer or total malignancies in adults with rheumatoid arthritis treated with a TNF inhibitor. There were, however, more patients who developed malignancies while treated with a TNF inhibitor compared to placebo or methotrexate, but it was not statistically significant.  

In rheumatoid arthritis patients who had a history of breast cancer, those treated with TNF inhibitors did not have have more breast cancer recurrence than patients who were not treated with TNF inhibitors, according to results published online in the Annals of the Rheumatic Disease (August 8, 2014).  


TNF-alpha Antagonism and Cancer Risk in Rheumatoid Arthritis: Is Continued Vigilance Warranted? Hyon Ju Park. Discovery Medicine. March 27, 2012.

Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Askling J. et al. Pharmacoepidemiol Drug Saf 20(2):119-130, 2011.

Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis. Mariette X et al. Annals of the Rheumatic Diseases. 70(11):1895-1904, 2011.

The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Wolfe and Michaud. Arthritis and Rheumatism 56(5):1433-1439, 2007b.

What's the Link Between Rheumatoid Arthritis and Cancer? Arthritis Special Report. Johns Hopkins. November 30, 2009.

Risk of Breast Cancer and Total Malignancies in Rheumatoid Arthritis Patients Undergoing TNF-alpha Antagonist Therapy: A Meta-analysis of Randomized Control Trials. Liu Y. et al. Asian Pacific Journal of Cancer Prevention. 2014.

TNF Inhibitor Therapy and Risk of Breast Cancer in Patients With Rheumatoid Arthritis: A Nationwide Cohort Study. Annals of the Rheumatic Diseases. Published online 8/8/14.

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