What Rheumatologists Need to Know About Cancer Risk in Rheumatoid Arthritis

In the United States, the lifetime risk of developing cancer is 1 in 3 individuals.¹ For patients with rheumatoid arthritis (RA), this risk may be increased due to the shared etiology between cancer and RA and the immunomodulatory nature of agents commonly used in RA treatment.²

When determining appropriate therapeutic options for patients with RA and cancer, providers must make complex decisions, often with limited data and conflicting recommendations.

Inconsistent Trends for Cancer Risk in RA

In a meta-analysis, which included pooled data from previous research published between 1990 and 2007, study authors indicated a 10% increase in the risk for cancer in patients with RA compared with the general population (standardized incidence ratio [SIR], 1.09; 95% CI, 1.06-1.13). However, this risk was not consistent across all cancer types.^2,3

Patients with RA were at highest risk for lymphoma and lung cancer. The SIRs for lymphoma were 2.46 (95% CI, 2.05-2.96) for malignant lymphoma, 3.21 (95% CI, 2.42-4.27) for Hodgkin disease, and 2.26 (95% CI, 1.82-2.81) for non-Hodgkin lymphoma. The SIR for lung cancer was 1.64 (95% CI, 1.51-1.79). The increased risk for lymphoma and lung cancer may be due to inflammation that is known to be common to RA. Etiologies common to both RA and cancer, such as genetics, smoking, and other lifestyle factors, may also be involved.²

There was no consistent trend in the risk for other cancers such as melanoma, prostate cancer, and cervical cancer in patients with RA. For breast and colorectal cancers, there was a decreased risk among patients with RA compared with the general population.²

Findings from studies assessing the risk for cancer from disease-modifying antirheumatic drugs (DMARDs) have often found to be mixed and inconclusive.⁴ However, studies have shown increased risk for nonmelanoma skin cancer in patients receiving biologic DMARDs (bDMARDs), specifically tumor necrosis factor inhibitors (TNFi).⁴On the other hand, research evaluating RA and cancer risk often include patients receiving treatment with DMARDs, therefore making accurate assessments of the risks difficult. In addition, because DMARDs are often used progressively or in combination therapy, distinguishing the risks between the different DMARDs have also been challenging.

Managing RA in Patients With Cancer – Are DMARDs Safe?

The management of RA in patients with cancer may be challenging and complex. Regarding the safety of DMARDs in patients with prior or concomitant cancer, conventional DMARDs (csDMARDs) are generally thought to be safe.^4,5 But for bDMARDs and targeted synthetic DMARDs (tsDMARDs), well-controlled data are lacking, partly because patients with cancer are often excluded from clinical trials due to concerns about potential adverse events on tumor immunity.⁴

Limited data that are available show that patients with RA who have received treatment with bDMARDs (both TNFi and non-TNFi) had a numerical, but nonsignificant, increase in risk for new or recurrent cancer, particularly nonmelanoma skin cancer.⁴ However, more data are needed to evaluate the safety of bDMARD and tsDMARD treatment during the different cancer stages and types.

Lopez-Olivo and colleagues⁵ evaluated consensus recommendations that may be useful to rheumatologists while managing RA in patients with cancer.

Conventional synthetic DMARDs (methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine): These drugs have been considered generally safe for use in patients with active or a previous history of cancer, if there are no drug interactions.^4,5 However, in patients with a history of lymphoma, the Canadian Rheumatology Association has advised caution against using leflunomide and methotrexate.⁶

Biologic DMARDs (TNFi and non-TNFi):
- For patients with active cancer, bDMARDs, especially TNFi agents, are not recommended. Some studies considered the use of rituximab and abatacept on a case-by-case basis, depending on the type of cancer.⁵
- For patients with cancer who have been treated more than 5 years previously, bDMARDs can be used with caution. Similarly, non-TNFi agents can also be used with caution. Rituximab has also generally been considered safe.⁵
- In patients with premalignant conditions, bDMARDs and cyclosporine are contraindicated or should be used with caution. Rituximab is an exception and may be considered in patients with in situ cancer.⁵

Targeted synthetic DMARDs (Janus kinase inhibitors): Few clinical guidelines exist on the use of tsDMARDs. Given the limited data, it is recommended that these agents should not be used in patients with active cancer, but can be considered in patients with a past diagnosis and no evidence of disease for at least 5 years.⁴

For the management of patients with RA and recently diagnosed cancer within the past 5 years, most guidelines suggest that DMARDs should be used in consultation with an oncologist.⁵ In their study, Pundole and Suarez-Almazor⁴ added that the clinical recommendations do not provide adequate guidance in all cases. Treatment decisions should be made using a shared decision-making process that includes factors such as age, type of cancer, stage of the disease, prognosis, and patient values.

Treating Cancer in Patients With RA

Treatment of RA is frequently discontinued in patients who are receiving cancer therapy because cancer may be considered a priority over conditions like RA, and also due to limited data and the lack of clinical guidelines.⁷

Overall, cancer treatments including surgery, chemotherapy, radiation, and immunotherapy increase the risk for complications in patients with RA. A cautious approach and careful monitoring for adverse outcomes such as infection, drug interactions, and toxicity are recommended.⁴

In Summary

Patients with RA are at higher risk for lymphoma and lung cancer.
It is unclear whether DMARDs increase the risk for cancer in patients with RA, though a higher risk for nonmelanoma skin cancer with bDMARDs, especially TNFi, has been described in some studies.
Patients with RA should follow the nationally recommended screenings for breast, cervical, endometrial, colorectal, lung, and prostate cancers. It may be beneficial to monitor patients with RA more closely for skin cancer.
All DMARDs may be safe to use in patients with RA and a past diagnosis of cancer who have had no evidence of disease for at least 5 years.
Conventional DMARDs are generally considered safe in patients with active cancer in the past 5 years. However, owHoqleflunomide and methotrexate are not recommended in patients with a history lymphoma.
For patients with a recent history of cancer of less than 5 years, TNFi agents are not recommended. Non-TNFi agents should be used with caution, except for rituximab, which is considered safe.
More data are needed to understand the effects of bDMARDs and tsDMARDs on cancer outcomes in patients with RA and active cancer.
Patients with RA undergoing cancer treatment should be carefully monitored for adverse outcomes, such as infection, toxicity, and drug interactions.
Management of patients with both RA and cancer should consider the type of cancer, stage, prognosis, life expectancy, and patient values. Providers should work with patients in a shared decision-making process to determine the best treatment approach.

References

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551
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(1):212. doi:10.1186/s13075-015-0728-9
Smitten AL, Simon TA, Hochberg MC, Suissa, S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10(R45). doi:10.1186/ar2404
Pundole X, Suarez-Almazor ME. Cancer and rheumatoid arthritis. Rheum Dis Clin N Am. 2020;46(3):445-462. doi:10.1016/j.rdc.2020.05.003
Lopez-Olivo MA, Colmegna I, Karpes Matusevich AR, et al. Systematic review of recommendations on the use of disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and cancer. Arthritis Care Res. 2020;72(3):309-318. doi:10.1002/acr.23865
Bombardier C, Hazlewood GS, Akhavan P, et al. Canadian Rheumatology Association recommendations for the pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs: Part II Safety. J Rheumatol. 2012;38(8):1583-1602. doi:10.3899/jrheum.120165
Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. doi:10.1007/s40744-017-0064-4