Addressing the Increased Risk for Malignancy in Rheumatoid Arthritis

Findings from various studies indicate that the overall risk for malignancy is higher among patients with rheumatoid arthritis (RA) compared with the general population.^1,2 The incidence of cancer may be highest within the first several years after RA diagnosis.^3,4  

The following observations have been noted in patients with RA compared with the general population:

• An overall reduced risk for breast, gastrointestinal, liver, and colon cancers,⁵ but with worse prognosis associated with these cancers; for example, 40% higher mortality among people with RA and breast cancer vs people from the general population who have breast cancer⁶

• Worse cancer-related mortality and prognosis for squamous cell carcinoma, hematopoietic malignancies, and cancers of the upper aerodigestive tract and prostate; for instance, 50% higher mortality among patients with both RA and prostate cancer vs people who do not have RA and have prostate cancer⁶
• Increased incidence of lung cancer, with worse survival prognosis⁵
• Increased risk for lymphoproliferative malignancies, including Hodgkin and non-Hodgkin lymphoma (NHL), with similar survival rates for NHL compared with people with NHL from the general population, whereas lymphomas in patients with RA “are more likely to be low grade and mortality less likely to be lymphoma related,” wrote the authors⁵

Although some data suggest that disease-modifying antirheumatic drugs (DMARDs) may increase the risk for cancer, it does not appear that these agents increase the overall risk. However, certain traditional DMARDs may increase the risk for specific cancers. For example, azathioprine has been linked with an increased risk for lymphoproliferative and other malignancies in patients with RA, and cyclophosphamide has been found to increase the risk for hematologic malignancies, urinary tract and bladder cancers, and other malignancies.

Additionally, although methotrexate does not appear to increase the overall incidence of lymphomas, it “may have divergent effects on lymphoma development, decreasing the development of some lymphomas via decreased RA-related immunologic activity (which is linked to lymphoma development) and promoting other lymphomas through immunosuppression, leading to an overall null impact on incidence,” as explained in one paper.⁵

RA and the therapies used to manage the disease have been associated with increased malignancy risk, thus presenting a significant challenge to researchers attempting to elucidate these connections.

For further insight into the relationship between RA and malignancy risk, Rheumatology Advisor interviewed one of the authors of the Rheumatology and Therapy article, Eric L. Matteson, MD, MPH, chair of rheumatology and professor of medicine at the Mayo Clinic in Rochester, Minnesota, and Laura Cappelli, MD, MHS, assistant professor of medicine in the division of rheumatology at Johns Hopkins School of Medicine in Baltimore, Maryland.

Rheumatology Advisor: What is known about the risk for malignancy in RA and the potential underlying mechanisms?

Dr Matteson: RA is associated with a greater than twofold increased risk for lymphoma. This risk is higher in patients with high disease activity and with more severe disease, including extraarticular involvement. This risk is related to the pathobiology of the underlying rheumatic disease, including the inflammatory burden, immunologic defects such as overexpression of Bcl-2 oncogenes, traditional risk factors such as smoking, and in some cases, associated viral infection.

Dr Cappelli: Patients with RA have some increased risk for lymphoma and lung cancer compared with the general population. This risk appears to be related to having RA itself rather than with the use of biologic medications, as recent large studies have shown. The mechanisms behind this risk are not well understood but probably have to do with immune dysregulation in RA leading to decreased tumor surveillance or chronic inflammation, which is a known risk factor for some cancers. Patients on immunosuppression therapy, regardless of their autoimmune disease, are at some increased risk for nonmelanoma skin cancer.

Rheumatology Advisor: In light of these findings, what are the top takeaways for clinicians?

Dr Matteson: With respect to management of the inflammatory disease, it is imperative to achieve optimal disease control and the lowest level of clinical disease activity possible using the least intensive treatment regimen available.

Patients for whom immunomodulatory therapy, including nonbiologic and biologic DMARDs, is being contemplated, should undergo routine cancer screening that is appropriate to their age, sex, familial cancer burden, and risk factors such as smoking.

Dr Cappelli: Patients with RA, like the rest of the population, should avoid smoking. Counseling your patients who smoke about the importance of smoking cessation is a key part of any clinic visit. Patients should go to the dermatologist yearly for skin cancer screening. Rheumatologists should make sure their patients are up to date on age- and sex-appropriate cancer screening. If there are unusual symptoms, such as unexplained weight loss, night sweats, lymphadenopathy, or fevers, an evaluation for underlying malignancy may be warranted.

Rheumatology Advisor: What should be the focus of future research in this area?

Dr Matteson: [Further investigation is needed regarding] identification of patients at high risk, the pathobiology of the immune system and how it contributes to the risk for cancer, and development of treatment strategies to reduce this risk.

Dr Cappelli: Future research should focus on defining the underlying mechanisms by which RA contributes to cancer risk so that they can potentially be addressed early in a patient’s course. Whether patients with certain autoimmune diseases could benefit from expanded cancer screening is also a very important area of inquiry.

References

1. Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015;17:212.
2. Gridley G, Klippel JH, Hoover RN, Fraumeni JF Jr. Incidence of cancer among men with the Felty syndrome. Ann Intern Med. 1994;120(1):35-39. 
3. Huang W-K, Chiou M-J, Kuo C-F, Lin Y-C, Yu K-H, See L-C. No overall increased risk of cancer in patients with rheumatoid arthritis: a nationwide dynamic cohort study in Taiwan. Rheumatol Int. 2014;34(10):1379-1386. 
4. Chen Y-J, Chang Y-T, Wang C-B, Wu C-Y. The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan. Arthritis Rheum. 2011;63(2):352-358. 
5. Wilton KM, Matteson EL. Malignancy incidence, management, and prevention in patients with rheumatoid arthritis. Rheumatol Ther. 2017;4(2):333-347.
6. Nayak P, Luo R, Elting L, Zhao H, Suarez-Almazor ME. Impact of rheumatoid arthritis on the mortality of elderly patients who develop cancer: a population-based study. Arthritis Care Res (Hoboken). 2017;69(1):75-83.