INTRODUCTION
Rheumatoid arthritis (RA) is a systemic autoimmune disease requiring treatment with immunosuppressive agents. Proper management of RA includes the use of disease-modifying anti-rheumatic drugs (DMARDs) to control systemic and local inflammation [
1,
2]. Recently, development of biological DMARDs, including tumor necrosis factor inhibitors (TNFi), has enabled more effective disease activity control. Because of the proinflammatory role of TNF, treatment with TNFi has proven to be beneficial for RA patients with inadequate responses to conventional synthetic DMARDs (csDMARDs) [
3]. However, anti-TNF therapy has also raised safety concerns, because relative immune deficiency following TNF inhibition can increase the risk of infection and malignancy. Since TNF plays an important role in cancer pathogenesis, the risk for cancer during and after anti-TNF therapy has emerged as a major concern [
4,
5].
TNF was primarily identified as an anti-tumor factor in the serum of Bacillus Calmette-Guérin-infected mice treated with endotoxin [
6,
7]. Serum transfer from these mice to other mice with subcutaneously transplanted sarcomas reduced the size of tumors. Several subsequent studies also indicated that systemic administration of TNF could suppress tumor progression, whereas other studies revealed that downregulation of TNF paradoxically reduced tumor formation and metastasis [
4]. Like these preclinical studies, clinical trials were also inconclusive, with conflicting results regarding TNF effects on carcinogenesis. Both treatment with recombinant TNF and TNFi were found to be therapeutically ineffective in cancer patients [
4,
5].
Since TNFi has become available and widely used in RA patients, the risk for malignancy in patients treated with TNFi has been constantly studied. Earlier data from clinical trials indicated that the risk for malignancy was greater in RA patients treated with TNFi than in TNFi-naïve patients [
8]. However, these studies were limited by small sample sizes and heterogeneous study populations. The majority of subsequent studies based on a large national registry suggested that overall cancer incidence did not increase during or after anti-TNF therapy [
9-
12].
Despite substantial previous research, efforts to elucidate the association between anti-TNF therapy and cancer are still ongoing. Because cancer incidence is influenced by genetic predisposition and environmental factors, cancer epidemiology differs between continents and countries [
13]. Thus, it is desirable to estimate cancer incidence from a nationwide database. In South Korea, the national healthcare system provides insurance coverage for nearly all citizens. All hospitals and medical institutions submit insurance claims to the Health Insurance Review and Assessment Service (HIRA), which reviews all insurance claims and makes decisions regarding payment [
14]. Because the submitted data include information about diagnosis and treatment for all citizens, the HIRA database can be used to obtain nationwide medical information.
In this study, we used the HIRA database to evaluate malignancy risk in RA patients following anti-TNF therapy. The incidence of all cancers and common cancers were compared in RA patients treated with TNFi or csDMARDs.
DISCUSSION
This study demonstrated that malignancy incidence was similar in seropositive RA patients treated with TNFi and those treated with csDMARDs. The IRRs adjusted for age, gender, and observational period revealed that the incidence for all cancers and site-specific cancers did not differ significantly between the groups.
To our knowledge, this is the first study comprising all citizens to investigate the cancer incidence in RA subsequent to anti-TNF therapy. A single study conducted in Taiwan included all citizens treated with TNFi [
12]. The Taiwanese study also used their National Health Insurance Database, and selected matched controls from patients treated with csDMARDs. We were able to minimize the drop-out that affects the detection of cancer occurrence by using the HIRA database, because all citizens were registered in the HIRA database. Inclusion of all citizens requires proper selection of study population. Previously, Cho et al. [
16] suggested that selecting patients according to diagnosis codes and prescribed drugs from the HIRA database was a reliable way to identify patients with RA. However, we could include only patients with seropositive RA, because of the reliability of diagnosis codes.
Previous studies have reported a wide range of cancer incidence rates, between 3.8 and 9.3 per 1,000 patientyears [
10-
12,
17,
18]. Estimation of cancer risk can vary due to ethnic diversity and environmental contributions [
13]. Excluding thyroid cancer, the crude cancer incidence in Korean RA patient was 8.2/1,000 patient-years. Because we included the diagnosis of carcinoma in situ, the estimated incidence would be relatively higher compared to the previous research. In a prior study conducted in Korea between 2001 and 2007, the overall cancer incidence in RA patients was 4.6/1,000 patient-years [
19]. This cancer occurrence could have been underestimated, because enrollment and follow-up for RA patients was limited to a single center. Nonetheless, the incidence was much lower than that identified in this study. This discrepancy may be due to differences in patient characteristics and study periods. The present study included a higher proportion of older and male patients, who develop cancers more frequently, according to the National Cancer Information Center [
20]. Moreover, cancer incidence has increased continuously in the general population since 2000, and the same trend should be expected in RA patients.
Previously, clinical studies investigating the association between anti-TNF therapy and cancer have shown inconsistent results. An initial-stage meta-analysis of clinical trials revealed increased cancer incidence in patients treated with adalimumab and infliximab [
8]. However, the observational period, ranging from 3 months to 1 year, was too short to evaluate the carcinogenic effects of TNFi. Subsequent observational studies with larger sample sizes and longer durations revealed similar cancer incidences, although there were controversies regarding several kinds of cancers [
21]. Recently, a Taiwanese nationwide cohort study demonstrated that cancer risk was lower in patients treated with anti-TNF therapy [
12]. The overall cancer incidence excluding hematologic malignancy and standardized incidence ratios for lung, breast, and genitourinary cancers were significantly lower in the biologics cohort [
12]. Our study also indicated that crude cancer incidence was lower in patients treated with TNFi than in those treated with cs- DMARDs. However, there were significant differences between the groups in clinical characteristics affecting cancer incidence, such as age, gender, and follow-up duration. When the IRRs were adjusted for age, gender, and observational period, incidence rates for all cancers and site-specific cancers were comparable in patients treated with csDMARDs and TNFi.
The pathogenesis of cancer is closely linked to inflammation and immunity [
22]. In general, chronic inflammation triggered by infection or autoimmunity can be a risk factor for cancer occurrence. In RA patients, longstanding disease and high disease activity were found to increase cancer risk, probably through chronic inflammatory response [
23,
24]. Thus, the effective control of inflammation by TNFi might reduce the cancer risk, although the effects of TNF on carcinogenesis are controversial [
5]. However, to elucidate causal links between anti-TNF therapy and cancer, further research will be required.
The most common cancer in all patients with RA was thyroid cancer, followed by lung cancer, stomach cancer, and colon cancer in descending order. The high incidence of thyroid cancer is in line with its incidence in the general population during the study period, due to increased medical surveillance [
25]. Except thyroid cancer, the most common site of cancer was lung in RA patients, whereas stomach cancer was most common in the general population during the study period. An increased risk for lung cancer in RA patients has been suggested by many previous studies [
26]. In this study, lymphoma was not detected among TNFi-treated patients.
The present study has several limitations. First of all, it was difficult to analyze the effects of other confounding variables, such as comorbidities, medications, and disease activity and duration. Information about comorbidities and medications was insufficient for further analysis due to the limitations of the database. Moreover, disease-specific features were not accessible, because of personal information protection. However, we assumed that the csDMARDs group also had active RA requiring methotrexate, leflunomide, or combination of csDMARDs. Second, patients with seronegative RA were not included in the analysis. Third, the study period was 4 years, and the mean follow-up duration was 3.2 years, which is a relatively short period for evaluating TNFi effects on carcinogenesis. Finally, we did not compare cancer incidence between RA patients and the general population, due to limited HIRA database information and cancer statistics.
This study showed the nationwide cancer incidence in Korean patients with RA and evaluated the association between anti-TNF therapy and cancer risk, using the database of all citizens. However, we should be aware that this study provides only rudimentary information, which requires further evaluation using well-designed registry or cohort. Recently, the Korean College of Rheumatology has constructed a national biologics registry for safety evaluation in treatment with biologics [
27]. Forthcoming data from this nationwide registry will provide a better understanding of the association between biologic therapies and cancer.
In conclusion, the risk of malignancy did not differ significantly between RA patients treated with TNFi and those treated with csDMARDs based on the insurance claim data. In terms of malignancy, anti-TNF therapy may be an effective therapeutic option with an acceptable safety profile for patients with inadequate responses to csDMARDs. This will be illuminated more thoroughly in a prospective observational registry set up.