Cancer Chemotherapeutics in RA: A Complex Connection

Rheumatoid arthritis (RA), cancer, and cancer chemotherapeutics have an interesting relationship. Two common RA drugs, methotrexate and rituximab, debuted as cancer therapies.¹ In the 1950s, methotrexate was the first drug shown to cure cancer in a patient with a rare cancer of the female reproductive tract called gestational choriocarcinoma. Currently, the cure rate for this type of cancer is nearly 100% in specialty cancer centers when detected before metastasis. This discovery resulted in the development of chemotherapy as treatment for solid tumors.

When rituximab was approved by the US Food and Drug Administration in 1997 as a therapy for non-Hodgkin lymphoma, it became the first monoclonal antibody to receive approval as a cancer therapy and the first single agent approved for lymphoma treatment.² Today, these medications are frequently used in the management of patients with RA.

In general, individuals with RA carry a higher risk of developing cancer. For example, studies have found that the risk for lymphoma is approximately 2-fold in individuals with RA compared with the general population, which is likely due to chronic inflammation.³ Lung cancer risk is also elevated in patients with RA.

In other research, certain drugs that are occasionally used for RA, including azathioprine and cyclophosphamide, have been linked to an elevated risk for cancer in patients with RA. Methotrexate has also been implicated in the risk for lung cancer, melanoma, and non-Hodgkin lymphoma.⁴ The overall risk is low, however, and the safety record and well-established benefits associated with methotrexate in RA often outweigh such risks.

Adding another layer to the cancer-RA connection is emerging evidence demonstrating that patients treated for cancer with checkpoint inhibitors have an increased risk of developing inflammatory arthritis.^5,6 Additionally, “other cancer chemotherapeutics, such as aromatase inhibitors used to treat breast cancer, may actually cause joint and musculoskeletal pain,” said Kimberly Liang, MD, assistant professor of medicine in the division of rheumatology at the University of Pittsburgh Medical Center in Pennsylvania. “Clinicians should be aware that certain cancer chemotherapeutics may have side effects that could mimic RA symptoms” or increase feelings of achiness in patients with RA, she told Rheumatology Advisor.

To further explore the association between cancer, RA, and cancer chemotherapeutics, Rheumatology Advisor spoke with Mary C. Nakamura, MD, rheumatologist and professor of medicine in residence at the University of California, San Francisco.

Rheumatology Advisor: What is known about the links between RA and cancer chemotherapeutics?

Dr Nakamura: While there are case reports of patients developing RA in association with cancer treatment with standard chemotherapeutic agents, there are also reports of patients developing RA associated with the development of cancer before treatment. We do not completely understand how RA is initiated, so it is difficult to completely attribute the cause to specific actions of these specific drugs. Standard cancer chemotherapeutic agents generally suppress the immune system and thus can dampen autoimmunity.  

In contrast, newer cancer immunotherapy medications stimulate the immune system. A recognized side effect of these therapies is autoimmunity and the development of an inflammatory arthritis similar to RA has been seen in a number of patients.  

Rheumatology Advisor: How are cancer chemotherapeutics currently used in RA? 

Dr Nakamura: Only 2 are regularly used to treat RA. Many other drugs tried in the past, including agents like chlorambucil, would not be used to treat RA today. The drugs currently used to treat RA, which are also chemotherapeutic agents, are methotrexate and rituximab. Methotrexate is used to treat cancer using much higher doses than those used to treat RA, so both the beneficial and adverse effects are generally different in scope and severity.

Rituximab is a monoclonal antibody that depletes CD20-expressing cells. B cell lymphomas can express CD20; thus, the drug was developed to treat lymphoma. Depletion of B cells using rituximab in autoimmunity has a number of effects on the immune system and has been shown to be effective to treat patients with RA. 

Rheumatology Advisor: What are the primary treatment implications for clinicians regarding this topic?  

Dr Nakamura: The main takeaways are:

• Dysregulation of the immune system is important in both autoimmunity and cancer. 
• Patients with RA have, at baseline, an increased risk of developing non-Hodgkin lymphoma compared with the general population. 
• An uncommon adverse event with methotrexate is the development of an Epstein-Barr virus (EBV)-associated lymphoproliferative disorder that can resolve with discontinuation of methotrexate. Therefore, in patients with RA on therapy who develop an EBV-associated lymphoproliferative disorder, a trial of discontinuation of immunosuppressive agents may be warranted before chemotherapy.
• Patients who receive the newer cancer immunotherapy medications for cancer treatment can develop a number of autoimmune syndromes, including RA. 

Rheumatology Advisor: What are the remaining questions that warrant further research in this area?  

Dr Nakamura: There are many issues that are actively being investigated, including: 

• What is the optimal treatment for autoimmunity in patients with RA with a history of cancer? 
• Is the risk for lymphoma in patients with RA decreased with optimal control of RA? 
• Are there specific risk factors in patients receiving cancer immunotherapy that predispose them to autoimmune side effects, particularly inflammatory arthritis? 
• What are the factors leading to the initiation of RA symptoms in high-risk patients? 

Interview has been lightly edited for style and clarity.

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References

1. National Cancer Institute. Treatment of solid tumor cancers with the chemotherapy drug methotrexate. www.cancer.gov/research/progress/discovery/methotrexate. Published April 30, 2014. Accessed August 20, 2018.
2. Grillo-López AJ, White CA, et al. Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol. 1999;26(5 Suppl 14):66-73.
3. Arthritis and Cancer Risk. www.arthritis.org/about-arthritis/types/rheumatoid-arthritis/articles/ra-cancer-risk.php. Accessed August 20, 2018.
4. 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):794-799.
5. Naidoo J, Cappelli LC, Forde PM, et al. Inflammatory arthritis: a newly recognized adverse event of immune checkpoint blockade. Oncologist. 2017; 22(6): 627-630.
6. Belkhir R, Burel SL, Dunogeant L, et al. Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment. Ann Rheum Dis. 2017;76(10):1747-1750.