The Risk of Cancer in Patients With Rheumatoid Arthritis: a Nationwide Cohort Study in Taiwan

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The risk of cancer in rheumatoid arthritis patients: a nationwide cohort study in Taiwan

Journal: Arthritis and Rheumatism Manuscript ID: ar-10-0893.R1

Wiley - Manuscript type: Full Length Date Submitted by the

Author: n/a

Complete List of Authors: Chen, Yi-Ju; Taichung Veterans General Hospital, Dermatology;

National Yang-Ming University, Faculty of Medicine

Chang, Yun-Ting; National Yang-Ming University, Faculty of Medicine

Wang, Chang-Bi; Taichung Veterans General Hospital, Division of Gastroeneterology

Wu, Chun-Ying; China Medical University, College of Public Health;

National Yang-Ming University, Faculty of Medicine; Taichung Veterans General Hospital, Division of Gastroeneterology Keywords: Cohort Study, Epidemiology, Rheumatoid Arthritis

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The risk of cancer in rheumatoid arthritis patients: a nationwide cohort study in Taiwan

Yi-Ju Chen, M.D., Ph.D.,

Yun-Ting Chang, M.D., Ph.D.,

Chang-Bi Wang, M.S.,

Chun-Ying Wu, M.D., Ph.D., M.P.H.

1

Department of Dermatology, Taichung Veterans General Hospital, Taichung;

2

Faculty of Medicine, National Yang-Ming University, Taipei;

3

Department of Dermatology, Taipei Veterans General Hospital, Taipei

4

Department of Public Health, College of Public Health, China Medical University, Taichung;

5

Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung;

Requests for reprints should be addressed to Chun-Ying Wu, MD, PhD, Faculty of

Medicine, National Yang-Ming University, and Division of Gastroenterology, Department

of Internal Medicine, Taichung Veterans General Hospital, No. 160, Sec. 3,

Taichung-Kang Rd. Taichung 407, Taiwan. TEL: +886-4-23592525, ext. 3304, FAX:

+886-4-22585686, E-mail: chun@vghtc.gov.tw

Key words: risk; cancer; rheumatoid arthritis; nationwide cohort study; Taiwan

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Word count: 2440

Table count: 4

Figure count: 0

Funding: Partly from TCVGH (Taichung Veterans General Hospital) research grant

Competing interests: The authors have no conflicts of interest to report.

Authorship: All authors had access to the data and a role in writing the manuscript

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Abstract

Objective: The association of rheumatoid arthritis (RA) and malignancy has been rarely

explored in Asian populations. We aimed to investigate the relative risk of cancer and to

identify high-risk group for cancer in RA patients.

Methods: We conducted a nationwide cohort study regarding the risk of cancer among

23,644 RA patients without prior history of malignancies, utilizing the national health

insurance database of Taiwan from 1996 to 2007. Standardized incidence ratios (SIR) of cancers were analyzed.

Results: A total of 935 cancers among RA patients were observed. There was an elevated

risk of cancer in RA patients (SIR 1.23, 95% confidence interval [CI] 1.22-1.23),

especially for hematologic malignancies (SIR 2.74, 95% CI 2.68-2.81). The relative risk of cancer was higher among younger patients, compared to the general population. Most

cancer cases were detected within the first year of diagnosis. The relative risk of cancer

decreased with observation time. The risk of non-Hodgkin’s lymphoma (NHL) was

greatest (SIR 3.54, 95% CI 3.45-3.63) among hematologic cancers. Among solid tumors,

the risk of cancers of kidney and vagina/vulva were of the most relevant. A decreased risk

of cancers of cervix and non-melanoma skin cancer in RA were also observed.

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Conclusions: RA patients are at increased risk of cancer, especially hematologic and

kidney cancers. The relative risk of cancer in RA patients decreased with long-term

follow-up. Cancer screening with continued vigilance is recommended.

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INTRODUCTION

Rheumatoid arthritis (RA) affects several organ systems including cardiovascular, musculoskeletal, respiratory and psychological systems, and leads to major

co-morbidities and mortality. Chronic organ damage and late complications, such as malignancy and cardiovascular diseases, have become major adverse factors of both morbidity and mortality.(1) However, the association of malignancies with RA remains controversial. Some studies have reported a similar (2-6) incidence of malignant diseases in RA patients compared to the general population; yet other reports have indicated a lower (7;8) risk of malignant diseases in RA patients. Most studies have consistently indicated an increased incidence of lymphoma(3;5;9;10) and a decreased incidence of

colorectal cancer in RA patients.(2;7;9) With relatively low prevalences of RA among Asian populations,(11-13) the relationship between malignancy and RA has rarely been

reported in these counties.(14)

The pathogenetic mechanisms of interaction between these two diseases remain uncertain. Baecklund et al.(15) firstly demonstrated high disease activity, rather than its treatment, to be a major determinant in lymphoma risk of RA patients. However, other factors such as treatment modalities may also be involved. (16) Our aim was to

investigate the relative risk of malignant diseases, including the specific cancer types,

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after the diagnosis of RA in Taiwanese population based on a nationwide cohort database.

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METHODS

Data sources

This study was based on data from the National Health Insurance Research Database (NHIRD) released by the National Health Research Institute (NHRI). Taiwan began its National Health Insurance (NHI) program in 1995 to finance health care for all of its residents. There are currently more than 25 million enrollees in the program, representing approximately 99% of Taiwan’s entire population. The database comprises

comprehensive information on insured subjects, such as demographic data, dates of clinical visits, diagnostic codes, details of prescriptions, and expenditure amounts, as detailed described in our previous studies.(17-21) International classifications of disease-9 (ICD-9) codes were used to define diseases during the study period. Personal information including family history, lifestyle and habits such as smoking and alcohol use was not available from the NHIRD.

Study subjects with RA

All study subjects were obtained from the Registry of Catastrophic Illness Database, a

subpart of the NHIRD. The insured who suffer from major diseases can apply for a

catastrophic illness certificate which grants exemption from co-payment. The

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applications of catastrophic illness certificates were validated by at least two specialists

based on careful examinations of medical records, laboratory and images studies. Only

those meet the diagnostic criteria of major diseases would be issued a catastrophic illness

certificate. RA and cancer are statutorily included in the catastrophic illness category.

Both outpatient and inpatient claims of beneficiaries with a catastrophic illness registry are collected in the catastrophic illness profile and distributed as a package. The

prescription claims of beneficiaries are released in a different dataset and is not included

in current catastrophic illness profile.

The patients with RA (ICD 9 code 714.0) were included between January 1, 1996 and December 31, 2005. Those younger than 16 years were excluded. All the included patients were followed-up until December 31, 2007 to make sure each included subject

has a sufficient observation time for at least 2 years. Application of catastrophic illness

certificate of RA requires a thorough clinical and laboratory survey which fulfills the

ACR (American College of Rheumatism) criteria.(22) Patients with other autoimmune

diseases such as SLE or Sjogren’s syndrome were excluded. Subjects with prior history

of malignancies were also excluded.

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As the data set used in this study consists of de-identified secondary data released to the public for research purposes, this study was exempt from full review by the

Institutional Review Board.

Identification of cancer cases

We identified the diagnoses of cancers with the records from the Registry of Catastrophic Illness Patient Database. To apply for a cancer catastrophic illness

certificate, cytological or pathological reports or evidence such as additional laboratory and image studies supporting the diagnosis of cancer, including tumor marker surveys, X ray, bone scan, CT scan or MRI scan, should be provided. At least two other oncologists will examine the medical records and laboratory information carefully including images

studies. Only those meet the criteria of diagnoses would be issued the certificates. We

excluded those with in-situ malignancies because in-situ malignant diseases do not qualify for a catastrophic illness certificate. The diagnostic codes of malignancies were defined as those from 140 to 208.91 in the ICD-9 revision clinical modification format.

We categorized these cancer cases into hematologic cancers and non-hematologic cancers.

Hematologic cancers were subcategorized into leukemias (coded 204-208) and

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lymphomas (including non-Hodgkin’s lymphoma [coded 200, 202-203] and Hodgkin’s lymphoma [coded 201]), according to the methods of the Cancer Registry in Taiwan.

Cancer risk and statistical analysis

All study subjects were followed up until a first time diagnosis of cancer, death, the end of follow-up in the medical records, or the end of 2007. We examined the

association between RA and specific cancer types with standardized incidence ratios (SIR). SIR was calculated as follows: the number of cancer cases among RA patients divided by the expected number of cancer cases according to national age-specific, gender-specific, and period-specific cancer rates. Yearly reports of cancer rates were obtained from the Taiwan National Cancer Registry. We pooled the 10-year cancer registry reports of Taiwan from 1996 to 2006 as a standard.

To assess the age effect on the relative risk of malignancies, we analyzed the relative risk among those aged 0-39, 40-69, and more than 70 years at RA diagnosis. A further analysis was done to evaluate whether the association of malignancies varied according to the time after RA diagnosis. We divided follow-up time into six periods: 1 year or less, 1-2 years, 2-4 years, 4-6 years, 6-8 years and more than 8 years.

The SAS statistical package (SAS System for Windows, version 9.1; SAS Institute,

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Cary, North Carolina) was used to perform the statistical analysis of the data in this study.

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RESULTS

Risk of cancers in RA patients with no prior history of malignancy

We identified a total of 23,644 patients with RA who did not have previous

malignancies. The mean age ± standard deviation (SD) among patients at diagnosis of RA was 53.08 ± 14.38 years. There were 18,527 (78.36%) female and 5,117 (21.64%) male patients among RA study group. The mean follow-up time for RA was 5.90 ± SD 2.87 years (Table 1). During the observation time of 139,555.47 person- years, a total of 935 cancers among RA were identified after diagnosis of disease. A slightly increased overall cancer risk in RA was observed (SIR 1.23, 95% confidence interval [CI] 1.22-1.23) (Table 2). Women and men were at similar risk of developing cancer.

The relative risk of cancer was greatest among younger patients with RA, and the

risk ratio reduced with age (Table 2). The SIR was 2.35 (95% CI 2.28-2.42) among those younger than 40 years old. The SIRs reduced to 1.58 (95% CI 1.56-1.59) among those aged between 40-69 years, and 1.03 among those older than 70 years old.

Malignant diseases in RA were mostly detected following the first year of diagnosis (SIR 58.96, 95% CI 58.13-59.96). The risk ratios gradually reduced with observation time.

(Table 2) After 8 years of follow-up, the SIR of malignancies in RA fell to 0.31, less than

that of general population.

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Specific types of non-hematologic cancers associated with RA

Excluding hematologic cancers, a slightly increased risk of non-hematologic malignancies (SIR 1.12, 95% CI 1.11-1.13) was also observed. (Table 4) The highest risks were cancers originating from kidney and female genitalis, such as vulva and vagina.

(Table 4) Other significantly associated cancers in RA included cancers originating from nasopharynx, melanoma, thyroid gland and lung. (Table 4)

On the contrary, a reduced risk of certain cancers was also observed, including cancers of colorectum, cervix and non-melanoma skin cancers. (Table 4)

Lymphohematopoietic cancers associated with RA

Among all comorbid malignant diseases, there were 75 cases (8.02%) of

hematologic malignancies including 59 cases of non-Hodgkin’s lymphoma (NHL), one case of Hodgkin’s lymphoma (HL) and 15 cases of leukemia. A significantly elevated risk for lymphohematopoietic malignancies in RA was observed (SIR 2.74, 95% CI

2.68-2.81), especially in male patients. (Table 2) The risk of cancer varies by age.

Middle-aged patients (aged 40-69 years) were at greatest relative risk for hematologic cancers, compared to general population with similar ages. (Table 2)

The risks for lymphohematopoietic cancers were extraordinarily high following the

first 2 years of diagnosis. The relative risk of hematologic cancer reduced with

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observation time. (Table 2) The SIR fell to 0.62 after 8 years of follow-up.

In regards to specific cancer types, the risk of NHL (including other lymphosarcoma, reticulosarcoma, multiple myeloma and other immunoproliferative neoplasms) was

greatest (SIR 3.54, 95% CI 3.45-3.63), followed by HL (SIR 1.76, 95% CI 1.45-2.17) and

leukemia (SIR 1.48, 95% CI 1.41-1.56). (Table 3)

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DISCUSSION

This is the first large scale nationwide study to estimate the risk of cancer in RA patients with no prior history of malignancies based on a Taiwanese population.

Consistent with prior cohort studies, the risks of lymphohematopoietic cancers including HL, NHL and leukemia are significantly higher in RA patients than in the general

population. In addition to lymphohematopoetic cancers, RA patients are at higher risk of developing some less common cancers such as those of kidney, vulva, thyroid gland and nasopharynx than the general population.

Most cancer cases in our cohort were detected within the first 2 years after diagnosis.

Aggressive surveillance for cancer during that period may have resulted in a detection

bias. However, when cancer cases observed in the first 2 years were excluded, there was a

sustained elevated risk among RA patients until 8 years of follow-up, indicating a true

link between these two diseases. Although the association between malignancy and RA

remains controversial, the association of lymphoma with RA has been frequently

observed. In addition to common genetic factors between autoimmune diseases and

lymphomas, aberrant EBV expression, persistent inflammation, chronic activation of

autoimmune B cells and immunosuppressive therapy have been proposed to contribute to

lymphoma development.(23;24) The assessment of lymphoma risk in association with

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immunomodulating therapy in patients with autoimmune disease is complex due to the inability to distinguish therapy-related effects from effects of the disease itself. The relationship among methotrexate, (15;25-28) nonsteroidal anti-inflammatory drugs

(NSAID), aspirin(29;30) or corticosteroid(16;31;32) and lymphoma risk has been

explored among RA patients, yet without consistent results. We were not able to examine

this association since we did not have treatment information for the RA patients in our study.

The finding of younger RA patients with higher risks of cancer has not been reported until recently.(33) Since malignant diseases increase with age among the general

population (data not presented), it is reasonable that the higher prevalence of cancer cases among aged patients makes the difference in incidence non-significant between elderly RA patients and elderly subjects from the general population.

Most of the data from previous cohort studies have shown an average twofold risk of lymphoma in RA when compared with the general population.(3;34-36) Our results

demonstrated similar risks to those of previous studies for NHL (SIR 3.54), HL (SIR 1.76) and, to a lesser extent, leukemia (SIR 1.48) among RA patients. We did not subcategorize our NHL patients by subtype because standardized cancer estimates by specific

lymphoma subtypes were not available.

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Increased risks of various solid tumors were observed in our RA patients. In addition to lung cancer (SIR 1.23), significantly elevated risks for certain less common cancers were observed, such as those of the kidney (SIR 2.12), melanoma (SIR 1.47), thyroid gland (SIR 1.41), and nasopharynx (SIR 1.39). The findings of increased risks of these

cancers highlight the power of our present study to detect differences in rare cancers.

Cigarette smoking, possibly contributing to RA via the production of antibodies

recognizing citrullinated proteins,(37) is also a strong risk factor for cancers of lungs,

kidney(38) and urinary bladders.(39) Other factors linking lung cancer and RA have been

proposed including chronic inflammation(40) and the presence of interstitial lung disease(41;42). It was not until recently that an association between RA and kidney cancers was demonstrated. A cohort study in a South European population indicated that RA patients with lung or kidney cancer have a higher mortality rate than expected.(2) An elevated risk of vagina/vulva (SIR1.69) was observed in our RA patients, which may be explained by an increased prevalence of high risk human papillomavirus (HPV) infection

in RA patients.(43) Cytotoxic drugs and biologics such as tumor necrosis factor (TNF)- α blockade may also increase susceptibility to HPV infection in RA patients.(44)

Increased incidence of melanoma has been reported in RA patients treated with

methotrexate (45) and biologics.(6) Our study demonstrated an increased risk of

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melanoma. Yet, with only three cases of melanoma observed in our RA cohort, a longer

observation time or additional pharmacologic information may benefit in exploring the

link between these two diseases.

There are several limitations to our present study. First, we did not have personal information of patients, such as lifestyle, body mass index (BMI), smoking habit and alcohol use, family history of malignancy or other autoimmune diseases, or information regarding systemic treatment which may contribute to cancer risk. Second,

misclassification of diseases may happen based on an administrative database. To

minimize this bias, we only enrolled patients from the catastrophic illness profile who met the criteria of RA. The number of RA patients may therefore be underestimated.

Finally, most RA patients undergo regular physical and laboratory check-ups during observation. A surveillance bias may contribute to some of the increased frequency of

cancer in these patients.

However, our study provides important information. This is the first large scale nationwide cohort study of cancer and RA conducted in an Asian population. RA patients are at risk to develop certain cancers when compared with that in general population,

especially in younger patients. In addition to a high prevalence of lymphohematopoietic

cancers, especially NHL, an increased risk of several less common cancers, such as

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vagina/vulva, kidney, nasopharynx, prostate and melanoma were also observed. Finally, a gradual reduction of relative cancer risk in RA patients following observation time was observed. A decrease of disease activity, long term exposure to immunomodulatory drugs

or early mortality among patients with severe diseases or complicated with other

comorbidities may all contribute to a decreased trend in the relative risk of cancer.

Current treatments for RA in Taiwan are a combination of several immunomodulative

drugs, mainly prednisolone, various NSAID, methotrexate, and biologics (adalimumab or

etarnecept). Other DMARDs such as azathioprine, hydroxylcholoroquinine,

cyclophosphamide, mycophenolate mofetil, etc., are occasionally used. Since some of

these medications may result in end organ damage or cancer risks, the direct effect of

immunosuppressive treatment on cancer risk in RA patients need further studies.

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ACKNOWLEDGEMENT

This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and

managed by the National Health Research Institute. The interpretations and conclusions

contained herein do not represent those of the Bureau of National Health Insurance,

Department of Health or the National Health Research Institute.

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Reference List

(1) Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther 2009;

11(3):229.

(2) Abasolo L, Judez E, Descalzo MA, Gonzalez-Alvaro I, Jover JA, Carmona L.

Cancer in rheumatoid arthritis: occurrence, mortality, and associated factors in a South European population. Semin Arthritis Rheum 2008; 37(6):388-97.

(3) Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N et al.

Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis 2005; 64(10):1421-6.

(4) Chakravarty EF, Genovese MC. Associations between rheumatoid arthritis and malignancy. Rheum Dis Clin North Am 2004; 30(2):271-84, vi.

(5) Geborek P, Bladstrom A, Turesson C, Gulfe A, Petersson IF, Saxne T et al.

Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005; 64(5):699-703.

(6) Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum 2007;

56(9):2886-95.

(7) Cibere J, Sibley J, Haga M. Rheumatoid arthritis and the risk of malignancy.

Arthritis Rheum 1997; 40(9):1580-6.

(8) Kauppi M, Pukkala E, Isomaki H. Low incidence of colorectal cancer in patients with rheumatoid arthritis. Clin Exp Rheumatol 1996; 14(5):551-3.

(9) Thomas E, Brewster DH, Black RJ, Macfarlane GJ. Risk of malignancy among patients with rheumatic conditions. Int J Cancer 2000; 88(3):497-502.

(10) Franklin J, Lunt M, Bunn D, Symmons D, Silman A. Influence of inflammatory

polyarthritis on cancer incidence and survival: results from a community-based

prospective study. Arthritis Rheum 2007; 56(3):790-8.

For Peer Review

(11) Beasley RP, Bennett PH, Lin CC. Low prevalence of rheumatoid arthritis in Chinese. Prevalence survey in a rural community. J Rheumatol Suppl 1983;

10:11-5.

(12) Chou CT, Pei L, Chang DM, Lee CF, Schumacher HR, Liang MH. Prevalence of rheumatic diseases in Taiwan: a population study of urban, suburban, rural differences. J Rheumatol 1994; 21(2):302-6.

(13) Shichikawa K, Inoue K, Hirota S, Maeda A, Ota H, Kimura M et al. Changes in the incidence and prevalence of rheumatoid arthritis in Kamitonda, Wakayama, Japan, 1965-1996. Ann Rheum Dis 1999; 58(12):751-6.

(14) Yamada T, Nakajima A, Inoue E, Tanaka E, Taniguchi A, Momohara S et al.

Incidence of malignancy in Japanese patients with rheumatoid arthritis.

Rheumatol Int 2010.

(15) Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F et al.

Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 2006; 54(3):692-701.

(16) Hellgren K, Iliadou A, Rosenquist R, Feltelius N, Backlin C, Enblad G et al.

Rheumatoid arthritis, treatment with corticosteroids and risk of malignant

lymphomas: results from a case-control study. Ann Rheum Dis 2010; 69(4):654-9.

(17) Wu CY, Kuo KN, Wu MS, Chen YJ, Wang CB, Lin JT. Early Helicobacter pylori eradication decreases risk of gastric cancer in patients with peptic ulcer disease.

Gastroenterology 2009; 137(5):1641-8.

(18) Chen YJ, Wu CY, Huang YL, Wang CB, Shen JL, Chang YT. Cancer risks of dermatomyositis and polymyositis: a nationwide cohort study in Taiwan. Arthritis Res Ther 2010; 12(2):R70.

(19) Wu CY, Wu CH, Wu MS, Wang CB, Cheng JS, Kuo KN et al. A nationwide population-based cohort study shows reduced hospitalization for peptic ulcer disease associated with H pylori eradication and proton pump inhibitor use. Clin Gastroenterol Hepatol 2009; 7(4):427-31.

(20) Wu CY, Wu MS, Kuo KN, Wang CB, Chen YJ, Lin JT. Effective reduction of

For Peer Review

23

Helicobacter pylori-infected patients. J Clin Oncol 2010; 28(18):2952-7.

(21) Huang YL, Chen YJ, Lin MW, Wu CY, Liu PC, Chen TJ et al. Malignancies associated with dermatomyositis and polymyositis in Taiwan: a nationwide population-based study. Br J Dermatol 2009; 161(4):854-60.

(22) Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31(3):315-24.

(23) Smedby KE, Askling J, Mariette X, Baecklund E. Autoimmune and inflammatory disorders and risk of malignant lymphomas--an update. J Intern Med 2008;

264(6):514-27.

(24) Smedby KE, Baecklund E, Askling J. Malignant lymphomas in autoimmunity and inflammation: a review of risks, risk factors, and lymphoma characteristics.

Cancer Epidemiol Biomarkers Prev 2006; 15(11):2069-77.

(25) Bachman TR, Sawitzke AD, Perkins SL, Ward JH, Cannon GW.

Methotrexate-associated lymphoma in patients with rheumatoid arthritis: report of two cases. Arthritis Rheum 1996; 39(2):325-9.

(26) Mariette X, Cazals-Hatem D, Warszawki J, Liote F, Balandraud N, Sibilia J.

Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002; 99(11):3909-15.

(27) Salloum E, Cooper DL, Howe G, Lacy J, Tallini G, Crouch J et al. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 1996;

14(6):1943-9.

(28) Georgescu L, Quinn GC, Schwartzman S, Paget SA. Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment.

Semin Arthritis Rheum 1997; 26(6):794-804.

(29) Kato I, Koenig KL, Shore RE, Baptiste MS, Lillquist PP, Frizzera G et al. Use of

anti-inflammatory and non-narcotic analgesic drugs and risk of non-Hodgkin's

lymphoma (NHL) (United States). Cancer Causes Control 2002; 13(10):965-74.

For Peer Review

(30) Cerhan JR, Anderson KE, Janney CA, Vachon CM, Witzig TE, Habermann TM.

Association of aspirin and other non-steroidal anti-inflammatory drug use with incidence of non-Hodgkin lymphoma. Int J Cancer 2003; 106(5):784-8.

(31) Zhang Y, Holford TR, Leaderer B, Zahm SH, Boyle P, Morton LM et al. Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in Connecticut United States women. Cancer Causes Control 2004; 15(4):419-28.

(32) Sorensen HT, Mellemkjaer L, Nielsen GL, Baron JA, Olsen JH, Karagas MR.

Skin cancers and non-hodgkin lymphoma among users of systemic

glucocorticoids: a population-based cohort study. J Natl Cancer Inst 2004;

96(9):709-11.

(33) Parikh-Patel A, White RH, Allen M, Cress R. Risk of cancer among rheumatoid arthritis patients in California. Cancer Causes Control 2009; 20(6):1001-10.

(34) Ekstrom K, Hjalgrim H, Brandt L, Baecklund E, Klareskog L, Ekbom A et al.

Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. Arthritis Rheum 2003; 48(4):963-70.

(35) Franklin J, Lunt M, Bunn D, Symmons D, Silman A. Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis. Ann Rheum Dis 2006; 65(5):617-22.

(36) Gridley G, McLaughlin JK, Ekbom A, Klareskog L, Adami HO, Hacker DG et al.

Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993; 85(4):307-11.

(37) Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun 2010; 34(3):J258-J265.

(38) Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol 2010; 7(5):245-57.

(39) Jacobs BL, Lee CT, Montie JE. Bladder cancer in 2010: how far have we come?

CA Cancer J Clin 2010; 60(4):244-72.

(40) Siemes C, Visser LE, Coebergh JW, Splinter TA, Witteman JC, Uitterlinden AG et

al. C-reactive protein levels, variation in the C-reactive protein gene, and cancer

For Peer Review

25

risk: the Rotterdam Study. J Clin Oncol 2006; 24(33):5216-22.

(41) Walker WC, Wright V. Pulmonary lesions and rheumatoid arthritis. Medicine (Baltimore) 1968; 47(6):501-20.

(42) 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.

(43) Rojo CW, Montoya FH, Gamez Nava JI, Suarez Rincon AE, Vazquez SJ, Padilla RM et al. [Prevalence and cervical human papilloma virus associated factors in patients with rheumatoid arthritis]. Ginecol Obstet Mex 2008; 76(1):9-17.

(44) Kim SY, Solomon DH. Tumor necrosis factor blockade and the risk of viral infection. Nat Rev Rheumatol 2010; 6(3):165-74.

(45) Buchbinder R, Barber M, Heuzenroeder L, Wluka AE, Giles G, Hall S et al.

Incidence of melanoma and other malignancies among rheumatoid arthritis

patients treated with methotrexate. Arthritis Rheum 2008; 59(6):794-9.

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Table 1. Demographic data of RA patients

RA N=23,644 (%) Mean age at diagnosis (SD) 53.08 (14.38) Age

15-39 4,295(18.17)

40-69 16,338(69.10)

70 3,011(12.73)

Gender

Male 5,117(21.64)

Female 18,527(78.36)

Mean follow-up year (SD) 5.90 (2.87)

N, number; SD, standard deviation.

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Table 2. SIRs and 95% CIs of cancers, according to age, gender, duration of follow-up of RA patients in Taiwan

*All cancers including hematologic cancers; SIR, standardized incidence ratio, 95%

CI, 95% confidence interval;

All cancers* Hematologic cancers

Characteristics

Observed Expected SIR 95% CI Observed Expected SIR 95% CI

All 935 762.19 1.23 1.22-1.23 75 27.35 2.74 2.68-2.81

Gender

Female 634 535.40 1.18 1.17-1.19 39 18.90 2.06 2.00-2.13

Male 301 228.13 1.32 1.30-1.33 36 8.23 4.38 4.23-4.52

Age, years

15-40 43 18.33 2.35 2.28-2.42 2 1.30 1.54 1.33-1.77

40-69 698 442.85 1.58 1.56-1.59 52 14.90 3.49 3.40-3.59

70 194 188.66 1.03 1.01-1.04 21 7.22 2.91 2.79-3.04

Follow-up, yrs

< 1 160 2.71 58.96 58.13-59.96 14 0.10 139.08 132.76-147.53

1-2 150 8.25 18.19 17.89-18.48 13 0.30 42.67 41.01-45.75

2-4 246 102.85 2.39 2.36-2.42 17 3.71 4.59 4.37-4.81

4-6 165 156.57 1.05 1.04-1.07 18 5.62 3.21 3.06-3.35

6-8 128 165.15 0.78 0.76-0.79 7 5.88 1.19 1.10-1.28

≧8 86 273.97 0.31 0.31-0.32 6 9.72 0.62 0.57-0.67

For Peer Review

Table 3. SIR of hematopoietic malignancies in RA in Taiwan

Cancer types Observed Expected SIR 95% CI

All 75 27.35 2.74 2.68-2.81

Leukemia 15 10.12 1.48 1.41-1.56

Hodgkin’s lymphoma 1 0.56 1.76 1.45-2.17

Non-Hodgkin’s

lymphoma and others*

59 16.66 3.54 3.45-3.63

SIR, standardized incidence ratio; CI, confidence interval.

*Others include lymphosarcoma, reticulosarcoma, multiple myeloma and other

immunoproliferative neoplasms

For Peer Review

Table 4. SIRs of non-hematologic malignancies and specific cancer types of RA patients in Taiwan

Specific cancer types Observed Expected SIR 95% CI

All cancers 860 769.30 1.12 1.11-1.13

Kidney 30 14.17 2.12 2.04-2.19

Others‡ 26 14.42 1.80 1.73-1.87

Vulva/vagina† 5 2.96 1.69 1.54-1.84

Nasopharynx, sinus, ears 22 15.79 1.39 1.34-1.45

Lung and mediastinum 123 90.47 1.36 1.34-1.38

Thyroid gland 23 16.28 1.41 1.36-1.47

Prostate 22 16.82 1.31 1.25-1.36

Stomach 54 42.93 1.26 1.22-1.29

Skin cancer

Melanoma 3 2.04 1.47 1.31-1.65

NMSC¶ 20 22.93 0.87 0.83-0.91

Uterus 20 15.68 1.28 1.22-1.33

Breast 123 101.44 1.21 1.19-1.23

Liver and gallbladder 126 108.59 1.16 1.14-1.18

Urinary bladder 26 22.51 1.15 1.11-1.20

Esophagus 11 10.01 1.10 1.03-1.17

For Peer Review

†Vulva/ vagina tumors including other unspecified female genital organs

‡Other tumors include malignancies of salivary glands, intestine, retroperitoneum, bone, cartilage, and connective tissue.

¶ NMSC, non-melanoma skin cancer

Pancreas 15 13.86 1.08 1.03-1.14

Oropharynx and larynx 31 29.26 1.06 1.02-1.10

Cancer of ill-defined sites 14 13.79 1.02 0.96-1.07

Ovary 14 14.27 0.98 0.93-1.03

Colon and rectum 102 107.99 0.94 0.93-0.96

Brain 5 5.34 0.94 0.86-1.02

Cervix 45 52.14 0.86 0.84-0.89