Cancer, cardiovascular disease, and respiratory conditions are among the leading causes of death in rheumatoid arthritis (RA).1 Consequently, numerous studies to date have focused on assessing the risk for these comorbidities in RA. Still, not enough is known about which factors lead to an increased risk for certain types of cancer in patients with RA.

The lung is one of the most common sites of extra-articular manifestations in RA.2 According to the Arthritis Foundation, an estimated 10% of people with RA will develop interstitial lung disease (ILD) over the course of their disease. However, it is not clear if the presence of ILD predisposes them to also develop lung cancer. Emerging study results are increasingly suggesting a potential association between the two.3

In 2 literature reviews and meta-analyses that compared the risk for overall malignancy and site-specific malignancies among patients with RA and the general population, patients with RA were found to be at a modest increased risk for overall malignancy and increased risk for lymphoma and lung cancer.4,5 The age- and sex-adjusted standardized incidence ratio (SIR) was used to quantify the relative risk for malignancy in RA compared with the general population.4

The total pooled SIR for studies reviewed in both meta analyses was 2.46 for malignant lymphoma, with a slightly greater SIR for Hodgkin lymphoma (3.21) compared with non-Hodgkin lymphoma (2.26).5 The total pooled SIR was 1.64 for lung cancer, also indicating an increased risk for this malignancy in RA.5 Both studies found a decreased risk for colorectal and breast cancers.4,5 Several factors, including male sex, older age, and seropositivity for rheumatoid factor and/or anti-citrullinated protein antibody (ACPA), have been suggested as potential risk factors for lung cancer in RA.6


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The association between lung cancer and RA remains an active research area in need of additional answers. We interviewed Sandeep Krishna Agarwal, MD, PhD, associate professor and section chief of the department of immunology, allergy, and rheumatology at Baylor College of Medicine in Houston, Texas, to discuss lung cancer risk in RA.

How much is known about the factors that may contribute to the increased risk for lung cancer in RA?

Sandeep K. Agarwal, MD: Some of this risk is likely attributable to smoking, which has also been associated with the development of RA. I think that some of the risk is also attributable to patients getting a lot of clinical tests and x-rays and being evaluated, but, at the end of the day we think that inflammation, especially lung inflammation, in RA patients may also increase the risk of cancer. Overall, the risk is small, but it is slightly higher [in patients with RA] and there are several studies showing this, but not every study has been able to confirm these findings.

How are the lungs affected by RA?

Dr Agarwal: The lungs are thought to be involved in RA in a number of ways. One is a hypothesis that suggests that some of the immune-mediated changes in RA and, in particular, the process called citrullination, may start in the lungs. Patients with RA can also get inflammatory pneumonitis and fibrosis, which is related to their disease.

Are there any specific screening recommendations for lung disease or lung cancer in patients with RA?

Dr Agarwal: Usually, patients with RA get a chest x-ray as part of their workup. In terms of monitoring for ILD, the primary screening protocols include screening patients for symptoms of breathlessness or shortness of breath and cough, in addition to routine physical exams that include examination of the lungs. There are no guidelines that recommend annual chest x-rays or computed tomography (CT) scans to screen for ILD or lung cancer in RA patients.

Have you noticed an increased incidence of lung cancer in your own clinical experience with RA patients?

Dr Agarwal: No, but as an individual doctor, one sees too few patients to clearly see these small but real risks in their patients. You have to think about this as the community at large, where large groups of patients, [such as those] in studies, show these risks.

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Do immunosuppressive medications used to treat RA contribute to cancer risk?

Dr Agarwal: There are some studies suggesting an increased risk of non-melanoma skin cancers with some of the biologics, but those studies are also controversial.  Methotrexate has been associated with a very small risk of certain forms of lymphoma. 

What types of studies are still needed to better understand the risk factors for lung cancer in RA?

Dr Agarwal: You need large studies of cohorts of patients that are followed for many years to understand these risks and to be able to control for all the different variables that might be contributing to cancer risk. Smoking is the largest one when we think about [risk for] lung cancer, but medications, age, and demographics all need to be considered. This can be done through large cohort studies.

References

1.      Widdifield J, Paterson JM, Huang A, Bernatsky S. Causes of death in rheumatoid arthritis: how do they compare to the general population? Arthritis Care Res. 2018;70(12):1748-1755.

2.      Demoruelle MK, Wilson TM, Deane KD. Lung inflammation in the pathogenesis of rheumatoid arthritis. Immunol Rev. 2020;294(1):124-132.

3.      Kakutani T, Hashimoto A, Tominaga A, et al. Related factors, increased mortality and causes of death in patients with rheumatoid arthritis-associated interstitial lung disease [published online June 7, 2019]. Mod Rheumatol. doi:10.1080/14397595.2019.1621462

4.      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(2):R45.

5.      Simon TA, Thompson A, Ghandi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015;17(1):212.

6.       Fragoulis GE, Chatzidionysiou K. Lung cancer in rheumatoid arthritis. Is there a need for better risk assessment and screening? Clin Rheumatol. 2020;39:957-961.