O R I G I N A L A R T I C L E
Malignancies associated with systemic lupus erythematosus
in Taiwan: a nationwide population-based cohort study
Ji-An Liang•Li-Min Sun• Jun-Jun Yeh•Wan-Yu Lin•Shih-Ni Chang•Hung-Chang Sung •
Chia-Hung Kao
Received: 30 June 2010 / Accepted: 14 November 2010 Ó Springer-Verlag 2010
Abstract Patients with systemic lupus erythematosus (SLE) are suggestive to have a higher cancer risk. The aim of this study is to evaluate the possible association of malignancy and SLE in Taiwan. We used the data of the National Health Insurance system of Taiwan to assess this issue. The SLE cohort contained 2,150 patients, and each patient was randomly frequency matched to 8 people without SLE on age and sex. The Cox’s proportion hazard regression analysis was conducted to estimate the effects of SLE on the cancer risk. In patients with SLE, the risk of developing overall cancer was marginally significantly higher [adjusted Hazard ratio (HR) = 1.26, 95% confidence interval (95% CI) = 0.99–1.59] and was significantly higher for developing prostate cancer (adjusted HR = 3.78, 95% CI = 1.30–11.0). Our study unexpectedly found that
Taiwanese patients with SLE have a higher risk to develop prostate cancer.
Keywords Malignancy Systemic lupus erythematosus Prostate cancer
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs predominantly in young women. It has numerous immunological and clinical manifestations and mainly involves the skin, kidneys, joints, mucous mem-branes, blood vessel walls, and nervous system. Because of the improvement of modern therapeutic and diagnostic resources, its prognosis is much better now. The life expectancy of such patients has improved from an approximate 4-year survival rate of 50% in the 1950s to a S.-N. Chang and C.-H. Kao contributed equally to this work.
J.-A. Liang
Department of Radiation Oncology,
China Medical University Hospital, Taichung, Taiwan J.-A. Liang W.-Y. Lin C.-H. Kao
School of Medicine, College of Public Health, China Medical University, Taichung, Taiwan L.-M. Sun
Department of Radiation Oncology, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan
J.-J. Yeh
Pingtung Christian Hospital and MeiHo University, Pingtung, Taiwan
W.-Y. Lin
Department of Nuclear Medicine,
Taichung Veterans General Hospital, Taichung, Taiwan
W.-Y. Lin
Institute of Radiological Science,
Central Taiwan University of Science and Technology, Taichung, Taiwan
S.-N. Chang (&) H.-C. Sung Management Office for Health Data,
China Medical University Hospital, Taichung, Taiwan e-mail: [email protected]
S.-N. Chang H.-C. Sung
Institute of Environmental Health, College of Public Health, China Medical University, Taichung, Taiwan
C.-H. Kao (&)
Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan e-mail: [email protected]
15-year survival rate of 80% today [1–3]. As a result of the increasing survival in patients with SLE, the incidence of chronic comorbidities, such as malignancy, had been rising [4]. This phenomenon also aroused investigators to evalu-ate the issue of the association between SLE and cancer [5–
12]. Almost all studies reported that malignancy in patients with SLE may occur more commonly than in the general population. For most cohort studies, the parameter esti-mating cancer risk in SLE has been the standardized inci-dence ratio (SIR), which is the ratio of observed to expected cancer cases. The SIR estimates (for cancer overall) in these studies ranged from as low as 1.1 (95% confidence interval [CI] 0.7–1.6) [11] to as high as 2.6 (95% CI 1.5–4.4) [12]. Three largest cohort studies (sample size was more than 1,000) so far using tumor registry data as cancer ascertainment all found that the SIRs for all cancer overall were significantly higher [5–7]. For the specific cancer types, lymphoma, particularly non-Hodgkin lymphoma (NHL), is the most well-known to have the link with SLE. Again, the data from the three largest cohort studies demonstrated the SIR for NHL ranged from 2.9 (95% CI 2.0–4.0) [6] to 5.2 (95% CI 2.2–10.3) [7].
To the best of our knowledge, there are no large popu-lation-based studies discussing the relationship between malignancy and SLE in Taiwan. We would like to find if there is the same pattern of cancer risk for patients with SLE in Taiwan. These results presented in this paper were from a retrospective cohort study to assess if there is a higher risk of developing malignancy in patients with SLE. The original database was derived from the National Health Insurance (NHI) system in Taiwan.
Materials and methods Study population
The present study used the reimbursement claims data of the universal NHI system of Taiwan. The health insurance program has covered more than 96% of population and contracted with 97% of hospitals and clinics since the end of 1996. [13].
This study obtained the claims data consisting of reg-istries and claims reported from contracted health care facilities in the year of 1996–2008, from the National Health Research Institute (NHRI), Department of Health. We were able to use the encrypted identification number of each patient to link files, including the registry of medical facilities, details of inpatients orders, ambulatory cares, dental services, and prescriptions. The socio-demographic information for this study included gender, birth date, occupation, monthly income for premium estimation, and residential area were also available.
We used a sub-dataset composed of a one million insured population created by NHRI using a systematic random sampling method, with approximately 5% of the entire population included. Diagnoses were coded with The International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM).
Study subject
Our study identified newly diagnosed patients with SLE in the period of 1999–2002 from both ambulatory care and inpatient care as the exposure cohort (ICD-9-CM 710.0). For the comparison cohort, we randomly selected 8 insured people without SLE in the same period, frequency matched with the SLE cohort on age and sex. The age of each study subject was measured by the difference in time between the index date and the date of birth. Subjects with the history of malignant cancer (ICD-9-CM 140–230) diagnosed before index date were excluded. We finally included 19,357 subjects in this study.
Study end-point
We used the unique patient’s identification number to link study subjects to the registry for Catastrophic Illness Patient Database to identify the newly diagnosed of cancer as the outcome of this study. The diagnosis of cancer in National Health Insurance Research Database (NHIRD) needs histological confirmation and report in the Cata-strophic Illness Patient Database. Person-years of follow-up time were calculated for each person until cancer diagnosed or censored. The date of censoring was defined as: the date of study subjects died in follow-up period, the date of last withdrawal from NHI, or the date termination of the insured program.
Statistical analysis
The socio-demographic data, distributions of categorical age, gender, occupation, urbanization level, living region and income between patients with SLE and non-SLE patients were using Chi-square tests. We also calculated the incidence density with person-years by these variables in the SLE cohort and non-SLE cohort. The rate ratio of cancer was calculated by each variable.
The Cox’s proportion hazard regression analysis was conducted to measure the effects of SLE on the risk of cancer. Hazard ratio (HR) and 95% confidence interval (CI) were calculated in the model.
All data measurements were performed by SAS statis-tical software (version 9.1 for Windows; SAS Institute, Inc., Cary, NC, USA), and the significance level was set to be 0.05.
Result
Characteristics of the study subjects
Table1 compares distributions of demographic character-istics between the SLE cohort and the comparison cohort. There were more women subjects than men (77.4% vs. 22.6%). Most subjects were in 20–39 years of age (38.6% both in non-SLE cohort and non-SLE cohort). Patients with SLE were more likely to be white collar occupation (56.0% vs. 51.8%, P \ 0.0001), living in highest urbanization level (35.5% vs. 31.1%, P \ 0.0001) and central region (36.0% vs. 20.1%, P \ 0.0001), and have higher income (14.7% vs. 11.7%, P \ 0.0001).
Risk and crude rate ratio of cancer
Table2 shows the incident densities and crude rate ratio (RR) of cancer by the baseline socio-demographic status. The SLE cohort had a higher incidence of cancer than the non-SLE cohort (51.2 vs. 41.9 per 10,000 person-years, RR = 1.22). In both SLE and non-SLE cohort, the inci-dence densities of cancer were higher in men (64.4 vs. 57.5 per 10,000 person-years, RR = 1.12) than in women (47.5 vs. 37.4 per 10,000 person-years, RR = 1.27). Compared with non-SLE cohort, the RR of cancer was higher in youngest group (\20 years; 14.7 vs. 2.3 per 10,000 person-years, RR = 6.5) and oldest group (C80 years; 434.8 vs. 190.0 per 10,000 person-years, RR = 2.26).
Table 1 Comparisons in demographic characteristics between SLE patients’ cohort and non-SLE cohort in 1999–2002
Variables Total N = 19,357 SLE P value* No N = 17,207 Yes N = 2,150 n (%) n (%) n (%) Gender 0.99 Women 14,983 (77.4) 13,319 (77.4) 1,664 (77.4) Men 4,374 (22.6) 3,888 (22.6) 486 (22.6) Age, years 0.62 \20 2,340 (12.1) 2,080 (12.1) 260 (12.1) 20–39 7,468 (38.6) 6,639 (38.6) 829 (38.6) 40–59 6,099 (31.5) 5,428 (31.6) 671 (31.2) 60–79 3,069 (15.9) 2,713 (15.8) 356 (16.6) C80 381 (2.0) 347 (2.0) 34 (1.6) Occupation \0.0001 White collar 10,120 (52.3) 8,917 (51.8) 1,203 (56.0) Blue collar 6,657 (34.4) 6,017 (35.0) 640 (29.8) Others 2,580 (13.3) 2,273 (13.2) 307 (14.3) Urbanization level \0.0001 1 6,118 (31.6) 5,355 (31.1) 763 (35.5) 2 5,556 (28.7) 4,942 (28.7) 614 (28.6) 3 3,373 (17.4) 3,015 (17.5) 358 (16.7) 4 4,300 (22.3) 3,895 (22.6) 415 (19.3) Region \0.0001 North 8,852 (45.7) 7,973 (46.3) 879 (40.9) Central 4,227 (21.8) 3,454 (20.1) 773 (36.0) South 4,835 (25.0) 4,445 (25.8) 390 (18.1)
East and island 1,443 (7.5) 1,335 (7.8) 108 (5.0)
Income \0.0001
\15,000 7,812 (40.4) 6,938 (40.3) 874 (40.7)
15,000–29,999 9,215 (47.6) 8,255 (48.0) 960 (44.7)
C30,000 2,330 (12.0) 2,014 (11.7) 316 (14.7)
Urbanization level: 1 indicates the highest level of urbanization and 4 the lowest * Chi-square test
The further multivariate analysis for Cox’s proportional regression model showed that the HR of cancer was sig-nificantly greater in the SLE cohort than that in the non-SLE cohort when we adjusted for age and gender (model 2, HR = 1.27, 95% CI = 1.01–1.59) (Table3). However, after adjusting all the variables in Table1, the risk of cancer became marginally significantly higher in patients with SLE (Model 3, HR = 1.26, 95% CI = 0.99–1.59).
Furthermore, the specific analyses on hematological malignance, colorectal cancer, liver cancer, lung cancer, breast cancer and gynecologic cancer for women, and prostate cancer for men are presented in Table4. Compared to the men sub-jects without SLE in Cox’s proportional regression analysis, the adjusted HR of developing prostate cancer was 3.78 folds higher for patients with SLE (95% CI = 1.30–11.0), and
hematological malignancy had a marginally significantly higher rate for patients with SLE. We cannot observe any relationship between other types of cancer and SLE.
Discussion
In this large population-based study, we collected 2,150 patients with SLE from the NHRI of Taiwan. From the literature review regarding SLE and cancer, only 2 studies had more patients with SLE than the current study [14]. Our findings showed the overall cancer risk for patients with SLE is significantly higher when we did not adjust the variables or adjusted for age and gender. Because the demographic characteristics between SLE patients’ cohort Table 2 Comparisons of incidence density of cancer between cohorts with and without SLE by socio-demographic factor
Variables SLE Rate ratio
No Yes
N Cases Person-years Rate* N Cases Person-years Rate*
All 17,207 595 142,051 41.9 2,150 86 16,789 51.2 1.22 Gender Women 13,319 412 110,222 37.4 1,664 62 13,061 47.5 1.27 Men 3,888 183 31,829 57.5 486 24 3,729 64.4 1.12 Age, years \20 2,080 4 17,694 2.3 260 3 2,042 14.7 6.50 20–39 6,639 89 55,063 16.2 829 11 6,637 16.6 1.03 40–59 5,428 225 46,416 48.5 671 31 5,391 57.5 1.19 60–79 2,713 244 21,159 115.3 356 34 2,559 132.9 1.15 C80 347 33 1,719 192.0 34 7 161 434.8 2.26 Occupation White collar 8,917 260 74,168 35.1 1,203 44 9,542 46.1 1.32 Blue collar 6,017 259 49,261 52.6 640 20 4,954 40.4 0.77 Others 2,273 76 18,622 40.8 307 22 2,293 95.9 2.35 Urbanization level 1 5,355 168 44,352 37.9 763 30 5,953 50.4 1.33 2 4,942 173 40,953 42.2 614 23 4,853 47.4 1.12 3 3,015 97 24,877 39.0 358 11 2,826 38.9 1.00 4 3,895 157 31,869 49.3 415 22 3,158 69.7 1.41 Region North 7,973 250 65,732 38.0 879 29 6,683 43.4 1.14 Central 3,454 124 28,604 43.4 773 36 6,207 58.0 1.34 South 4,445 174 36,712 47.4 390 19 3,058 62.1 1.31
East and island 1,335 47 11,003 42.7 108 2 841 23.8 0.56
Income
\15,000 6,938 239 56,816 42.1 874 46 6,671 69.0 1.64
15,000–29,999 8,255 296 67,938 43.6 960 33 7,552 43.7 1.00
C30,000 2,014 60 17,297 34.7 316 7 2,566 27.3 0.79
and non-SLE cohort showed significant difference in the occupation, urbanization level, region, and income (Table1), and the rate ratio of cancer in patients with SLE also showed the difference by the 4 characteristics mentioned earlier (Table2), the model 3 which adjusted these variables is more appropriate to evaluate the rela-tionship between the SLE and cancer. By this model, our patients with SLE showed a marginally significantly higher rate for cancer with the HR of 1.26 and 95% CI is 0.99–1.59. The results are compatible with previous researches in both the magnitude and direction, indicating an overall increased risk of cancer among patients with SLE [5, 6,10, 12, 15].
Gayed et al. did a literature review to assess the existing evidence for the relationship and found patients with SLE have an increased susceptibility to cancer, and the trend of statistical significance seemed to be com-patible with the sample size [14]. The most powerful study to date is performed by Bernatsky et al. [5]. They collected 9,547 patients with SLE from 23 centers for a total 76,948 patient-years and found 431 malignancies in an average 8-year follow-up. The SIR estimate was 1.15 (95% CI = 1.05–1.27) for all cancer combined.
We used the retrospective cohort study design for opti-mal flexibility and efficiency. The subjects for our com-parison cohort were randomly selected 8 insured people without SLE in the same period, frequency matched with each patient in the SLE cohort on age and sex. It is dif-ferent from the studies using the general population as the comparison group. The strength of this design is to clearly separate the study groups into with exposure (with SLE) and without exposure (without SLE), and use the group without SLE as the reference to compare. We used RR instead of SIR to estimate the risk. SIR was calculated as the ratio of observed to expected cancer cases. The general population used for comparison could include the patients with SLE as well; even the percentage is expected too small to affect the result.
The hematologic malignancy was the most well-know cancer type to be related to the SLE. Most data from the earlier studies strongly suggested an increase incidence of hematologic cancers in patients with SLE, especially in non-Hodgkin’s lymphoma [5, 7, 10–12]. This study found a marginally significantly higher risk for developing all the hematologic malignancies. The 95% CI became wider when we focused on non-Hodgkin’s lymphoma or Hodgkin’s disease, and both were not statistically significant (data not shown). Some studies found the increased occurrence for lung cancer and liver cancer in patients with SLE [5–7,15,
16]. Lung cancer and liver cancer are two common malig-nancies and led the first two cancer mortality in Taiwan [17]; therefore, we were interested in knowing if they are related to the SLE. Our data showed a 1.41 and 1.28 fold increased Table 3 Hazard ratios and 95 percent confidence interval of cancer
associated with SLE in Cox’s regression analysis (all cancer) Variables Model 1 Model 2 Model 3
HR (95% CI) HR (95% CI) HR (95% CI) SLE
No 1.00 (reference) 1.00 (reference) 1.00 (reference) Yes 1.27 (1.01–1.59)* 1.27 (1.01–1.59)* 1.26 (0.99–1.59) * Model 1 unadjusted
* Model 2 adjusted for age, gender
Model 3 adjusted for age, gender, area, occupation, urbanization, and income
* Significant difference
Table 4 Hazard ratios and 95 percent confidence interval of cancer associated with SLE in Cox’s regression analysis in different cancer Variable Multivariate model*
HR (95% CI) Hematological malignancy** SLE No 1.00 (reference) Yes 2.23 (0.95–5.24) Colorectal cancer SLE No 1.00 (reference) Yes 0.71 (0.30–1.65) Liver cancer SLE No 1.00 (reference) Yes 1.28 (0.66–2.47) Lung cancer SLE No 1.00 (reference) Yes 1.41 (0.70–2.84)
Breast cancer (women only) SLE
No 1.00 (reference)
Yes 0.78 (0.41–1.45)
Uterus, cervical, ovary, and vagina cancer SLE
No 1.00 (reference)
Yes 1.42 (0.66–3.03)
Prostate cancer (men only)
No 1.00 (reference)
Yes 3.78 (1.30–11.0)*
* adjusted for age, gender, area, occupation, urbanization, and income ** ICD-9-CM: hematological malignancy, 200.xx-203.xx and 205.xx-208.xx; colorectal cancer, 153.xx and 154.xx; liver cancer, 155.xx; lung cancer, 162.xx; breast cancer, 174.xx and 175.xx; uterus, cervical, ovary and vagina cancer, 179.xx-184.xx; prostate cancer, 185.xx
risk for lung cancer and liver cancer, respectively, but both are not statistically significant.
The current study showed a significantly higher risk for developing prostate cancer in patients with SLE. Most prior studies did not find the increased risk of prostate cancer in patients with SLE [5–7,18], or even a lower risk [19]. To the best of our knowledge, there was only one earlier paper presented a significantly higher risk. Nived et al. did a study from an inception cohort in southern Sweden and found the estimated SIR for prostate cancer was 6.41 with 95% CI = 1.3–18.7 [20]. The finding is contradicted to expectation because male patients with autoimmune dis-orders have increased levels of antibodies against the estrogen receptors, which may decrease the protective effect of estrogen for prostate cancer [21]. Some possible undetermined complex mechanisms between the relation-ship of SLE and prostate cancer are still needed to be explored and larger studies are mandatory before any fur-ther conclusions can be made.
In conclusion, this population-based retrospective cohort study found marginally significant increase in overall cancer and hematologic malignancies in Taiwanese patients with SLE, and unexpectedly identified significant increase in developing prostate cancer. The age-adjusted incidence rate of prostate cancer in Taiwan increased dramatically from 2002–2006, and it is currently the 5th commonest malignancy among Taiwanese male [17]. The findings may arouse the attention of NHI of Taiwan to reconsider the policy regarding follow-up and cancer screening in patients with SLE.
Acknowledgments This study was supported by the National Sci-ences Council, Executive Yuan (grant numbers NSC 95-2625-Z-039-002, NSC 96-2625-Z-039-003, NSC 97-2625-M-039-003, NSC 98-2621-M-039-001), China Medical University Hospital (grant number 1MS1) and Taiwan Department of Health, Clinical Trial and Cancer Research Centers for Excellence (grant number DOH99-TD-B-111-004, DOH99-TD-C-111-005).
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