INTRODUCTION
Rheumatoid arthritis (RA) is a chronic systemic disease characterized by joint inflammation resulting in articular destruction, requiring long-term treatment. RA is also associated with comorbidities and mortalities such as cardiovascular disease, infectious disease, osteoporosis, and malignancy.
The risk of malignancy is of considerable interest in RA patients because of its immunologic pathogenesis and immune therapeutic targeting in disease management using disease-modified antirheumatic drugs (DMARDs). A meta-analysis of the incidence of malignancy in RA as compared with in the general population [
1] found that RA patients appear to be at increased risk for both lymphoma and lung cancer [
2] but at lower risk for colorectal and breast cancers [
3,
4]. However, the findings of previous studies assessing the malignancy risk in RA patients are not consistent and there are disagreements demographically (e.g., age, sex), geographically, and nationally or according to variable definitions of cancer outcome. In China, the prevalence of malignancy within the Chinese Registry of Rheumatoid Arthritis (CREDIT) cohort was 0.6% and breast and lung cancers were the most common cancers [
5]. The factors associated with malignancy included advanced age and methotrexate (MTX) treatment in the CREDIT cohort. However, CORRONA, a United States-based registry of RA, revealed that the overall incidence of malignancy was 0.56 per 100 person-years (PY) and non-melanoma skin cancer was the most common type of cancer [
6]. In a comparative study of real-world RA populations [
7], the age-/sex-standardized incidence rates of malignancy per 100 PY in SRR (a Swedish registry) and NOAR (a United Kingdom registry) were 0.87 and 0.77, respectively.
Meanwhile, the occurrence of malignancy among patients with RA in South Korea has not been thoroughly investigated in a nationwide-based population study, despite the importance of understanding the underlying malignancy risk among patients with RA.
Therefore, we aimed to investigate the incidence and risk factors of malignancy in patients with RA using a large observational cohort, the Korean Observational Study Network for Arthritis (KORONA), which was conducted in the Clinical Research Center for Rheumatoid Arthritis involving 23 centers across South Korea [
8].
DISCUSSION
In this prospective cohort study of 5,023 patients with RA assessing the risk for developing malignancy, we provide several key insights into the current prevalence, incidence, and risk factors. First, we identified 103 malignancy patients, corresponding to a prevalence rate of 2.05%, during cross-sectional analysis. Second, we observed 64 newly developed malignancies during the follow-up period. Notably, the risks of stomach, colon, and lung cancers were decreased by 0.4−, 0.13−, and 0.35-fold, respectively. Third, we identified thyroid disease and RA disease duration as risk factors and HCQ use as a possible preventive factor in developing malignancy. This is the first study analyzing the prevalence, incidence, and risk factors of malignancy in a large observational prospective RA cohort in Korea.
In addition, we report that the SIR for overall malignancy in the RA cohort was decreased relative to that in the general population. Although, in one recent meta-analysis, the overall standardized incidence rate for overall malignancy was 10% increased in RA patients [
4] as compared with in the general population, individual studies have offered more inconsistent results. Some studies reported that the overall risk of malignancy was similar to that of the general population [
11–
13], while others confirmed less overall malignancy risk among patients with RA than the general population [
4,
14,
15]. From Korea, only two papers have been published concerning the malignancy risk in RA patients, with different results [
12,
16]. Lee [
16] demonstrated that the overall cancer incidence among Korean RA patients was increased, while Kim et al. [
12] showed that the incidence rate for cancer was not significantly increased from that of the general population. Both studies had limitations, having been performed in a single center with a limited information and short observational period. In contrast, the present study is the first large-scale nationwide investigation to estimate the risk of malignancy in a population of Korean patients with RA with no history of malignancy.
In previous studies from Western countries including meta-analyses [
1,
4], the overall risk for malignancy was not consistent in patients with RA, but the risk for site-specific malignancy was significantly varied from that in the general population. These included an increased risk of lymphoma [
17–
19] and lung cancer [
4,
18] and a reduced risk of colorectal and breast cancers [
1,
20]. In this study, during the follow-up period, one lymphoma case was observed in a male RA patient and seven lung cancers (four men, three women) were identified. The SIR for lymphoma and lung cancers was not increased in RA patients, inconsistent with the findings of previous studies. Smoking is a well-known independent risk factor for lung cancer and interstitial lung disease (ILD) would thus be a potential risk factor for lung cancer [
21,
22]. In the KORONA cohort, the majority of participants had never smoked (84.5%) and the proportion of patients with ILD was only 0.8%. Given that most studies to date have been conducted in Western countries, the lower smoking rate in the KORONA cohort is characteristic of Korean RA patients. Therefore, our results are likely to be linked to the low smoking and ILD rates in this study cohort.
Regarding site-specific malignancy, the incidence rates of stomach cancer (SIR, 0.41; 95% CI, 0.21 to 0.74) and colon cancer (SIR, 0.13; 95% CI, 0.03 to 0.37) were significantly decreased in RA patients as compared with in the general population in this study. In a recent meta-analysis [
4] and previous epidemiological studies [
11,
15,
20,
23], colorectal cancer displayed a decreased risk in RA patients as compared with in the general population, which is similar to as found in this study. It has been well noted that NSAIDs and aspirin reduce the risk of colorectal cancer [
24]. In one meta-analysis [
25], anti-inflammatory drug intake, especially cyclooxygenase (COX)-2 inhibitors, was associated with a statistically significant reduction in the risk of gastric cancer. NSAIDs inhibit the cyclooxygenase enzyme (COX-1 or COX-2) involved in the synthesis of prostaglandin, which are elevated in colorectal cancer. RA patients mostly use NSAIDs to reduce inflammation, which may impart a protective effect against the development of colorectal cancer.
The incidence of gastric cancer in patients with RA appears to be inconsistent. A Japanese cohort showed a lower risk for stomach cancer than that in the general population [
26], while a Taiwanese cohort showed an increased risk for stomach cancer (SIR, 1.26; 95% CI, 1.22 to 1.29) [
27]. In this study, the risk of stomach cancer with RA was decreased (SIR, 0.41; 95% CI, 0.21 to 0.74). There are significant known regional differences in gastric cancer incidence and mortality. Gastric cancer rates are significantly increased in East Asia, including in Korea [
28], and
Helicobacter pylori infection is one of the risk factors for gastric cancer as a carcinogen in Korea [
29]. A recent nationwide multicenter study in Korea [
30] reported a downward trend in
H. pylori seroprevalence and an increase in
H. pylori eradication, which could affect development of gastric cancer. In addition, RA patients tend to receive regular endoscopies due to their high gastrointestinal bleeding risk, leading to a greater chance to eradicate
H. pylori in this group than in the general population.
In our study, HCQ was indicated to be a potential protective factor against developing malignancy in RA patients. HCQ is usually used as component of a triple-drug combination involving MTX and sulfasalazine as well for RA treatment and is also widely used in the treatment of systemic lupus erythematous (SLE). As suggested in previous research [
31,
32], HCQ treatment in patients with SLE could reduce the risk of malignancy. It is also suggested that HCQ might have a role in preventing neoplasia in SLE. In our study, HCQ may have played a protective role against developing malignancy in RA patients, in contrast with a previous study [
33]. Interest has grown in highlighting the antitumoral effects of HCQ and chloroquine, which may be related to strong antiproliferative, antimutagenic, and lysosomotropic-autophagy inhibition effects [
34,
35]. However, given that HCQ monotherapy was found only in nonmalignant group and HCQ monotherapy is generally used for patients with low disease activity, it seems difficult to rule out the possibility that malignant group might have higher disease activity than nonmalignant group. Although statistically insignificant between two groups, it also raises a possibility that malignant group with higher disease activity have been treated with leflunomide, corticosteroids, or biologic DMARDs more frequently than nonmalignant group, resulting in similar disease activity.
The malignant group also tends to have higher monthly income than the nonmalignant group even though it is not statistically significant. Considering the fact that the most common diagnosed cancer is thyroid cancer, it is possible the malignant group with higher income levels could increase their chance of diagnosing cancer by accessing medical services, particularly in preventive health services, such as cancer screening.
Some limitations of this study should be mentioned. Precision in some of the analyses, particularly in the assessment of specific cancer types, was limited because the occurrence of malignancy was obtained through interviews and based on patient self-reports. Therefore, the existence of missing cases or inaccurate patient reports cannot be ruled out. Another limitation is selection bias due to some patients being lost to follow-up. Also, some patients may have been unable to visit the clinic regularly because their RA was exacerbated or comorbidities such as malignancy had worsened. This bias may be associated with an underestimation of malignancy incidence.
Still, our results suggest that the underlying disease independently informs the risk of malignancy. Indeed, we found that thyroid disease increased the risk of malignancy by 2.5-fold among patients with RA. Thyroid disease at baseline was demonstrated to be a risk factor for malignancy in RA patients in our analysis. Recently, Li et al. [
36] reported that the risk of thyroid dysfunction was increased among RA patients. In an Asian population, thyroid disorder increased the risk of breast cancer [
37]. In real practice, thyroid function testing is part of the regular medical checkup for RA patients. This might be one of the reasons for increased thyroid disease in RA patients.
No association was found between the incidence of overall malignancy and baseline measurements of disease severity, physical dysfunction, or medication use. Presumably, these baseline data reflect characteristics years after diagnosis and would change with subsequent treatment.
The greatest strength of this study is its use of real-world clinical data obtained from a large, observational cohort study on RA with a long duration of follow-up, thus providing more precise estimates of the malignancy risk in RA patients.
In conclusion, the overall incidence of malignancy in Korean patients with RA was demonstrated to be decreased as compared with in the general Korean population. Regarding site-specific cancer, the risk of stomach and colon cancers was decreased.