Prevalence of co-morbidities and evaluation of their

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ORIGINAL ARTICLE

Prevalence of co-morbidities and evaluation of their

monitoring in Korean patients with rheumatoid arthritis:

comparison with the results of an international, cross-sectional study (COMORA)

In Ah CHOI,

^1,

* Sung Hwan PARK,

²

Hoon-Suk CHA,

³

Won PARK,

⁴

Hyun Ah KIM,

⁵

Dae-Hyun YOO,

⁶

Han Joo BAEK,

⁷

Seong Geun LEE,

⁸

Yun Jong LEE,

⁹^‡

Yong Bum PARK,

¹⁰

Seung-Cheol SHIM,

^11,^†

Ihsane HMAMOUCHI

¹²

and Yeong Wook SONG

^1,13

1Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital,²Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital,³Division of Rheumatology, Department of Internal Medicine, Samsung Medical Center, Seoul,⁴Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Incheon,⁵Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang,⁶Division of Rheumatology, Department of Internal Medicine, Hanyang University Medical Center, Seoul,⁷Division of Rheumatology, Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon,⁸Division of Rheumatology, Department of Internal Medicine, Pusan National University Hospital, Busan,⁹Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam,¹⁰Division of Rheumatology, Department of Internal Medicine, Yonsei University Severance Hospital, Seoul,¹¹Division of Rheumatology, Department of Internal Medicine, Eulji University Hospital, Daejeon, Korea,¹²Rheumatology Department, Faculty of Medicine, Laboratory of Clinical Research and Epidemiology, El Ayachi Hospital, Mohammed V University, Rabat, Morocco,¹³Department of Molecular Medicine and Biopharmaceutical Sciences, Medical Research Center, Seoul National University, Seoul, Korea

Abstract

Aim:We designed this study to evaluate the prevalence of comorbidities, their monitoring states and association with treatment medication in Korean rheumatoid arthritis (RA) patients compared with patients from other countries.

Methods:We analyzed 1050 RA patients from 11 Korean centers and compared them with 3520 patients from 16 other countries using an international, cross-sectional study evaluating comorbidities of RA (COMORA) database.

Results:Annual evaluations of cardiovascular (CV) risk were less frequently performed in Korea (P= 0.0011).

The prevalence of CV-associated morbidity was similar between Korean and international RA patients, although the proportions of current smokers, patients with a family history of CV disease, patients with hyperlipidemia, and patients with Framingham score>20% were significantly lower in Korea (P<0.0001 for all), and the antiplatelet agents were more optimally used in Korea (P=0.0004). Prostate cancer screening was less frequently performed compared to other countries (P<0.0001). Less than 10% of Korean RA patients were given influenza and pneumococcal vaccinations according to current recommendations.

Correspondence: Professor Yeong Wook Song, Department of Internal Medicine, Seoul National University, College of Medicine, 101 Daehak-ro Jongno-gu, Seoul, 03087, Korea. Email: [email protected]

*Present address: Division of Rheumatology, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea

†Present address: Division of Rheumatology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea

‡[Correction added on 19 May 2017, after first online publication: author name has been corrected to “Yun Jong Lee.”]

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Conclusions:There are differences in the prevalence of comorbidities and monitoring states of the risk factors between patients in Korea and in other countries. The prevalence of CV morbidity was similar between the two groups although the prevalence of CV risk factors was significantly low in Korea, suggesting that rheumatologists in Korea need to pay more attention to yearly CV risk monitoring, in addition to the screening of malignancy and vaccination of RA patients against infectious diseases.

Key words: cardiovascular diseases, comorbidity, neoplasms, rheumatoid arthritis.

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects synovial joints. In addition to articular pain and functional limitations, patients with RA can suffer from comorbidities.¹Some comorbidities, such as cardiovascular (CV) diseases, osteoporosis, infection and several types of cancer, are more frequently found in RA patients than in the general population; these conditions are associated with RA itself or with the medications used to treat it.^2–6 We designed this study to evaluate the prevalence of comorbidities and their monitoring states in Korean RA patients compared with patients from other countries using a database provided by an international, cross- sectional study evaluating comorbidities of RA (COMORA).⁷

MATERIALS AND METHODS

This cross-sectional, observational, multicenter, international study is an ancillary study of COMORA study and used already analyzed data from COMORA database. We analyzed the demographics, disease characteristics, comorbidities and health monitoring status of 1050 RA patients from 11 South Korean centers (Kor- ean cohort) and compared them with the 3520 patients from the other 16 countries using the COMORA database (international cohort included Argentina, Austria, Egypt, France, Germany, Hungary, Italy, Japan, Morocco, Netherlands, Spain, Taiwan, United Kingdom, Uruguay, United States, Venezuela).

The protocol was approved by the Seoul National Uni- versity College of Medicine-Seoul National University Hospital Institutional Review Board (IRB), Catholic University of Korea St. Mary’s Hospital IRB, Samsung Medical Center IRB, Inha University Hospital IRB, Hal- lym University Sacred Heart Hospital IRB, Hanyang University Medical Center IRB, Gachon University Gil Medical Center IRB, Pusan National University Hospi- tal IRB, Severance Hospital IRB and Eulji University Hospital IRB and the study was performed in accordance with the principles of the 1964 Declaration of

Helsinki. All persons gave their informed consent prior to their inclusion in the study.

Sample size

The original COMORA study (n=3920) included 400 patients randomly selected from 1050 Korean patients.

In this ancillary study, all 1050 Korean patients were analyzed and compared with the 3520 patients from the other 16 countries (3920 COMORA cohort minus 400 Koreans). Patient composition in international and Korean cohorts is summarized in Figure 1.

Data collected

A protocol specifically created for COMORA study was used to collect four categories of data, which were patient’s demographic characteristics, comorbidities, coexisting risk factors and compliance with current national recommendations regarding management of these comorbidities.⁷

Patient’s demographic characteristics included age, gender, body mass index, smoking status, alcohol intake, marital status, socioeconomic status and highest level of education completed. In addition, disease activity was assessed utilizing the disease activity score using 28 joints (DAS28)–erythrocyte sedimentation rate (ESR)^8,9 and medications used to treat RA were recorded.

Comorbidities consisted of ischemic CV disease (myocardial infarction, stroke), solid cancers (in colon, skin, lung, breast and uterus for women, prostate for men) and lymphoma, gastrointestinal diseases (diverticulitis, ulcers), infections (hepatitis), lung disease (chronic obstructive pulmonary disease [COPD], asthma) and psychiatric disorders (depression).

Risk factors for CV diseases consisted of hypertension, diabetes, dyslipidemia, family history of myocardial infarction in first degree relatives or sudden death in first degree relatives prior to age 55 in male relatives and prior to age 65 in female relatives. Hypertension was defined as: (i) those ever diagnosed as having hypertension and receiving anti-hypertensive therapy;

or (ii) systolic pressure >140 mmHg or diastolic

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pressure >80 mmHg; or (iii) >130 mmHg and 70 mmHg in the setting of concomitant diabetes mellitus.¹⁰Diabetes was defined as: (i) those ever diagnosed as diabetes and receiving therapy; or (ii) random blood glucose level >1.26 g/L.¹¹ Dyslipidemia was defined as: (i) those ever diagnosed as having dyslipidemia and receiving anti-dyslipidemia therapy; or (ii) low-density lipoprotein cholesterol above the targeted value defined with regard to the number of concomitant additional CV risk factors.¹² Compliance with current national recommendations regarding management of these comorbidities was also evaluated. For example, patients older than 50 years were considered to be managed optimally if they were receiving an antiplatelet agent in the setting of a past thrombotic CV event or if their Framingham risk score¹³ was calculated to be 20% or more after being adjusted for RA (multi- plied by a factor of 1.5).¹⁴

Risk factors for infectious diseases consisted of yearly dentist visit and vaccination status. A patient was considered to be monitored optimally for infectious diseases if he or she had: (i) a dental examination within the previous year; (ii) an influenza vaccination within the previous year; and (iii) a pneumococcal vaccination within the previous 5 years.¹⁵

Risk factors for cancers consisted of family history of prostate, breast or colon cancer, adenomatous polypo- sis and/or personal history of inflammatory bowel disease (for colon cancer) and history of numerous nevi (or skin cancers). A patient was considered to be monitored optimally for cancer if age- and sex-appropriate cancer screening recommendations for the general population were followed.

A patient was considered to have been screened optimally for osteoporosis if at least one bone densitometry study had been performed after the onset of RA and if he or she was taking vitamin D supplementation at the time of the study visit.¹⁶

For each patient, information was collected by a study investigator during a face-to-face interview at a dedicated study visit and through review of the medical record.

Statistical analyses

Statistical analyses were performed using SPSS version 14.0 (SPSS Inc., Chicago, IL, USA) and SAS version 9.1.3 (SAS Institute, Inc., Cary, NC, USA). Graphics were generated in R version 3.0.1 (http://www.r-projec- t.org/). All data are expressed as proportion (%) or mean (SD) as appropriate. Mean values of continu- ous variables were compared using Student’s t-test and proportions were compared using the chi-square test.

Logit models for binary data were used to calculate odds ratios. A P-value <0.05 was considered statisti- cally significant.

RESULTS

Baseline demographics and disease characteristics of RA patients

The baseline demographics and disease characteristics of RA patients are summarized in Table 1. Korean RA patients were less likely to be smokers or overweight and more likely to be married compared to the international cohort. They tended to have shorter disease duration and lower disease activity compared to the Figure 1 Patient composition in international and Korean cohorts. The original COMORA study (n=3920) included 400 patients randomly selected from 1050 Korean patients because a disproportionately high number of subjects were enrolled in South Korea compared with each of the other 16 countries (ranging from 30 to 411). In this ancillary study, all 1050 Korean patients were analyzed and compared with the 3520 patients from the other 16 countries (3920 COMORA cohort minus 400 Koreans).

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international cohort. The use of methotrexate was similar, glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) were more often and biologic disease- modifying antirheumatic drugs (DMARDs) were less often used in the Korean compared to the international cohort.

Prevalence of comorbidities

Prevalence of myocardial infarction, stroke, hepatitis B and gastrointestinal ulcers in the Korean cohort were not significantly different from the prevalence in the international cohort. Prevalence of basocellular skin cancer was significantly lower in Koreans but overall prevalence of solid cancers excluding basocellular skin cancer was not significantly different between the Kor- ean and international cohorts. Prevalence of hepatitis C, COPD, asthma and depression were significantly lower and prevalence of surgery for diverticulitis was higher in Koreans compared to the international cohort. Analysis of comorbidities is shown in Table 2.

Prevalence of risk factors for comorbidities Smoking, family history of CV disease and hyperlipidemia were less frequent in Korean RA patients while diabetes was more frequent. The proportion of patients with Framingham score >20% was significantly lower in Koreans compared to the international cohort.

The prevalence of family history of breast cancer and colon cancer were lower in Koreans. In addition, there

was no patient with a history of inflammatory bowel disease or large numbers of skin nevi (> 40) in the Kor- ean cohort (Table 3).

Management of comorbidities

Annual evaluations of cardiovascular risk, including measurements of blood pressure, serum creatinine, glucose and cholesterol were performed less in Kore- ans. More patients were receiving optimal antiplatelet therapy in Korea compared to the international cohort. Of the 52 patients who had a prior myocardial infarction or stroke, 34 (65.4%) were currently receiving an antithrombotic drug and 18 (34.6%) were not. Among the other 998 patients who had no history of myocardial infarction or stroke, 63 patients were good candidates for prophylactic antithrombotic drug treatment because they were over the age of 50 and had a calculated Framing- ham risk score above 20%; however, of these, 51 (81.0%) patients were not receiving any antithrombotic agents. Thus, a total of 69 patients (6.6%) enrolled in this study should have been treated with antithrombotic drug prophylaxis to prevent cardiovascular events but were not being managed optimally and this prevalence is significantly less than in the international cohort.

Of Korean RA patients, 36.5% received an influenza vaccination during the year before the study visit, although the international prevalence was lower Table 1 Baseline demographics and disease characteristics of rheumatoid arthritis patients

Variables Korean cohort

(n=1050)

International cohort (n=3520)

P-value

Female gender,n(%) 872 (83.1) 3191 (81.4) 0.1940†

Age, years, meanSD 5612 5613 0.6106‡

Smoking status,n(% current smokers) 82 (7.8) 503 (13.3) <0.0001†

Educational level,n(% university or graduate school) 252 (24.0) 941 (24.0) 0.9728†

Marital status,n(% married) 853 (81.2) 2698 (69.7) <0.0001†

BMIn, (% overweight or obese) 216 (20.6) 2021 (51.7) <0.0001†

Work statusn, (% currently employed) 304 (29.2) 1107 (31.7) 0.1362†

Disease duration, years 7.36.6 9.88.9 <0.0001‡

DAS28–ESR 3.51.4 3.81.6 <0.0001‡

HAQ 0.90.6 1.00.7 <0.0001‡

High disease activity (DAS28–ESR>5.1) 161 (15.3) 854 (24.3) <0.0001†

Clinical disability (HAQ>1.0) 110 (10.5) 646 (18.4) <0.0001†

Glucocorticoidn, (% currently taking) 765 (73.0) 1835 (52.1) <0.0001†

NSAID use,n(% having taken during previous 3 months) 825 (78.7) 1840 (52.5) <0.0001†

MTX,n(% ever treated) 933 (89.5) 3109 (88.3) 0.2687†

Any biological therapy,n(% ever treated) 143 (13.7) 1471 (41.8) <0.0001†

†chi-square test,‡student’st-test. BMI, body mass index; CRP, C-reactive protein; DAS28-ESR, Disease Activity Score of 28 joints–erythrocyte sedimentation rate; HAQ, Health Assessment Questionnaire; MTX, methotrexate; NSAID, nonsteroidal anti-inflammatory drug.

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(24.5%,P<0.0001). A pneumococcal vaccination had been given to only 11.1% of Korean patients within 5 years of the study visit, which is even less than in the international cohort (17.9%, P<0.0001). Both an influenza and a pneumococcal vaccination were given according to current recommendations in only 102 (9.7%) of patients.

Prostate and skin cancer screening were less frequently performed and lung and breast cancer monitoring were more frequent in Korean RA patients. Bone densitometry was more frequently done but vitamin D supplements were taken less in Korea compared to the international cohort (Table 4).

Table 2 Prevalence of investigated comorbidities in rheumatoid arthritis patients from Korea (Korean cohort) and 16 other countries (international cohort)

Korean cohort (n=1050)

P-value OR (95% CI)

Ischemic cardiovascular diseases

Myocardial infarction 35 (3.3%) 160 (4.6%) 0.1003† 0.72 (0.50–1.05)

Stroke 20 (1.9%) 63 (1.8%) 0.9281† 1.06 (0.64–1.76)

Any 52 (5.0%) 216 (6.1%) 0.1744† 0.80 (0.58–1.09)

Cancers Prostatic 3 (1.7%) 14 (2.2%) 0.2329‡ 0.80 (0.23–2.80)

Breast 16 (1.8%) 73 (2.6%) 0.2634† 0.71 (0.41–1.22)

Uterus 20 (2.3%) 57 (2.0%) 0.7013† 1.15 (0.68–1.92)

Colon 4 (0.4%) 33 (0.9%) 0.1151‡ 0.40 (0.14–1.14)

Melanoma 1 (0.1%) 22 (0.6%) 0.0584‡ 0.15 (0.20–1.12)

Basocellular 1 (0.1%) 81 (2.3%) <0.0001‡ 0.04 (0.01–0.29)

Any skin 1 (0.1%) 99 (2.8%) <0.0001‡ 0.03 (0.00–0.24)

Lung 5 (0.5%) 17 (0.5%) 1.000† 0.98 (0.36–2.67)

Lymphoma 10 (1.0%) 17 (0.5%) 0.1052† 1.98 (0.90–4.33)

Any solid 44 (3.2%) 240 (6.8%) 0.0025† 0.60 (0.43–0.83)

Any solid excluding basocellular cancer

43 (4.1%) 169 (4.8%) 0.3838† 0.85 (0.60–1.19)

Infections Hepatitis B 23 (2.2%) 104 (3.0%) 0.2388† 0.74 (0.47–1.17)

Hepatitis C 10 (1.0%) 76 (2.2%) 0.0235† 0.45 (0.23–0.88)

Gastro-intestinal diseases Surgery for diverticulitis 10 (1.0%) 12 (0.3%) 0.0196† 2.81 (1.21–6.52) Gastroduodenal ulcer 124 (11.8%) 373 (10.6%) 0.2930† 1.13 (0.91–1.40)

Pulmonary diseases COPD 15 (1.4%) 130 (3.7%) 0.0003† 0.37 (0.22–0.64)

Asthma 26 (2.5%) 255 (7.3%) <0.0001† 0.32 (0.21–0.49)

Psychiatric diseases Depression 44 (4.2%) 568 (16.6%) <0.0001† 0.23 (0.16–0.31)

†chi-square test,‡Fisher’s exact test. CI, confidence intervals; COPD, chronic obstructive pulmonary disease; OR, odds ratio.

Table 3 Prevalence of risk factors for CV diseases and cancer in rheumatoid arthritis patients from Korea (Korean cohort) and 16 other countries (international cohort)

Korean cohort (n=1050) International cohort (n=3520) P-value OR (95% CI)

Recent smokers† 121 (11.5%) 735 (21.5%) <0.0001‡ 0.47 (0.39–0.58)

Family history of CV disease 77 (7.3%) 527 (15.0%) <0.0001‡ 0.45 (0.35–0.58)

Hypertension 395 (37.6%) 1424 (40.5%) 0.1071‡ 0.89 (0.77–1.02)

Hypercholesterolemia 167 (15.9%) 1154 (32.8%) <0.0001‡ 0.39 (0.32–0.46)

Diabetes 195 (18.6%) 467 (13.3%) <0.0001‡ 1.49 (1.24–1.79)

Framingham score>20% 657 (37.4%) 1985 (43.6%) 0.0004‡ 0.77 (0.67–0.89)

Family history of prostatic cancer 2 (1.2%) 17 (2.7%) 0.3860§ 0.43 (0.10–1.88) Family history of breast cancer 25 (2.9%) 318 (11.6%) <0.0001‡ 0.23 (0.15–0.35) Family history of colon cancer 22 (2.1%) 242 (7.0%) <0.0001‡ 0.29 (0.18–0.45)

Personal history of IBD 0.0 55 (1.6%) - -

Skin nevi>40 0.0 149 (4.3%) - -

†Patients who have smoked in recent 3 months,‡chi-square test,§Fisher’s exact test. CI, confidence intervals; CV, cardiovascular; IBD, inflammatory bowel disease; OR, odds ratio.

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DISCUSSION

This study reveals differences in the prevalence of comorbidities and risk factor monitoring status between RA patients in Korea and in 16 other countries.

Several distinct characteristics of Korean patients were shown in this report, such as lower frequency of smoking or obesity and high frequency of married patients.

RA activity was lower and usage of biologic DMARDs was significantly less. This lower biologic usage would be co-joined with higher prevalence of steroids (73.9%) and NSAIDs use (78.6%).

There had been a prospective RA cohort in South Korea, the KORean Observational Study Network for Arthritis (KORONA), which was composed of 4721 patients from 23 institutions. Patients in KORONA were similar to the Korean cohort in this study in that there was a low prevalence of current smokers (8.01%) and biologics users (5.78%) and a high prevalence of NSAID users (81.03%) and steroid users (73.99%).¹⁷ KORONA also collected some data about the presence of comorbidities via patient interviews, such as hypertension and diabetes, but did not evaluate the risk factors for comorbidities or monitoring status of the comorbidities. Therefore, to the best of our knowledge, this is the first large-scale cohort study to address comorbidities in Korean patients with RA.

In this study, we found that vaccination for the prevention of infectious diseases or monitoring and primary prevention for CV disease are not conducted fully in accordance with current recommendations. Influenza and pneumococcal vaccination is provided free to

patients over 65 years in Korea. However, patients with RA are in need of annual influenza vaccination and pneumococcal vaccination even when they are under 65 years and rheumatologists in Korea need to be aware of their patients’ vaccination status and to assure their patients receive appropriate prevention.

In addition, the prevalence of CV morbidity was similar between Korean and international cohorts even though the prevalence of CV risk factors, especially the proportion of patients with Framingham score >20%

was significantly lower in the Korean cohort. We cannot explain the exact cause of this inconsistency in our results. Further studies investigating unknown risk factors or genetic contribution may be needed to explain this relatively higher prevalence of CV morbidity compared to the low prevalence of known risk factors. In fact, annual evaluations of cardiovascular risk, including measurements of blood pressure, serum creatinine, glucose and cholesterol were less frequently performed in the Korean cohort and it can provide a basis for the suggestion that Korean rheumatologists should pay more attention to risk monitoring and primary prevention for CV disease.

Lung cancer monitoring with chest X-ray and breast cancer monitoring with mammography, which are included in the national health screening program in Korea for people over 40 years of age,¹⁸were performed at optimal levels in Korean patients.

Skin cancer screening was performed significantly less frequently and prevalence of skin cancer was also significantly lower in the Korean cohort. There was only one case of malignant melanoma and no case of Table 4 Percentage of rheumatoid arthritis patients optimally monitored for the given comorbidities from Korea (Korean cohort) and 16 other countries (international cohort)

Korean cohort (n=1050)

P-value OR (95% CI)

Cardiovascular diseases

Risk yearly evaluation 569 (54.1%) 2105 (59.8%) 0.0011 0.79 (0.69–0.91) Optimal antiplatelet therapy 981 (93.4%) 3172 (90.1%) 0.0013 1.56 (1.19–2.04) Infections Yearly dentist visit 400 (39.4%) 1452 (42.3%) 0.1056 0.89 (0.77–1.02) Influenza vaccination 312 (30.6%) 814 (24.5%) 0.0001 1.36 (1.16–1.58) Pneumococcal vaccination 115 (11.1%) 592 (17.9%) <0.0001 0.57 (0.46–0.71)

Cancer diseases Prostatic 20 (15.4%) 192 (39.6%) <0.0001 0.28 (0.17–0.46)

Breast 264 (55.8%) 826 (50.5%) 0.0480 1.24 (1.01–1.52)

Uterus 419 (62.8%) 1222 (58.9%) 0.0772 1.18 (0.99–1.41)

Colon 186 (29.2%) 543 (26.7%) 0.2495 1.13 (0.93–1.37)

Skin 24 (2.3%) 899 (26.4%) <0.0001 0.07 (0.04–0.10)

Lung 1023 (97.9%) 3166 (90.2%) <0.0001 5.04 (3.25–7.80)

Osteoporosis Vitamin D supplementation 302 (28.8%) 1609 (45.7%) <0.0001 0.48 (0.41–0.56) Bone densitometry (at least once) 772 (73.5%) 1978 (56.2%) <0.0001 2.16 (1.86–2.52) P-values were calculated by chi-square test. CI, confidence intervals; OR, odds ratio.

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non-melanoma skin cancer in the Korean cohort.

There are possibilities of ignored cases of non-melanoma skin cancer in Korea due to lack of screening.

However, it is also true that the prevalence of skin cancer is quite low in the general Korean population and this may contribute to the low skin cancer screening rate in Korea. The age-standardized incidence rate (ASR) of malignant melanoma in the general Korean population was 1.0/100, 000 and ASR of non-melanoma skin cancer was 5.0/100 000 in 2013.¹⁹In comparison, ASR of malignant melanoma was 16.8/

100, 000 in men and 12.6/100, 000 in women among the general population of the USA and 13.7/

100, 000 in men and 15.6/100, 000 in women among the general population of the UK in 2012.²⁰ In the statistics of the International Agency for Research on Cancer, age-world-standardized incidence rate of malignant melanoma is significantly lower in east-Asia compared to the rest of the world.²¹Even in the statistics of the Centers of Disease Control and Prevention within US residents, skin cancer rates were different by race and ethnicity and Asian/Pacific Islan- ders had significantly lower incidence compared to all races.²²Prevalence of skin cancer is low in the general population of Korea but the incidence is continuously increasing.²³Therefore, it is better for Korean rheumatologists to pay attention to the monitoring of skin cancer.

Prostate cancer monitoring was also less often performed in Korean patients, suggesting that more attention to prostate cancer monitoring is warranted.

There are several limitations to this study. First, the Korean cohort consisted of patients from 11 aca- demic hospitals across South Korea. Although they were regionally well distributed, all the centers were tertiary hospitals and the patients in these centers may not be representative of typical RA patients in Korea. The same weakness also exists in the international cohort and COMORA authors reported a potential weakness of inability to guarantee that all patients studied in the COMORA cohort (3920 patients) were fully representative of RA patients in the participating countries.⁷ Second, although this is the first large-scale cohort study concerning comorbidities in Korean RA patients, a cohort of 1050 patients is not large enough to analyze the prevalence of rare comorbidities such as malignancies. The prevalence of several solid cancers such as prostate, colon and skin cancer was too low to obtain a statis- tically significant odds ratio. Also, some of the risk factors of malignancy such as a history of

inflammatory bowel disease or an unusually large number of skin nevi (>40) did not exist in the Kor- ean RA cohort. Third, monitoring and prevention of osteoporosis and vaccination states were accessed but actual prevalence of osteoporosis, spine and hip frac- ture, tuberculosis and pneumonia were not included in the study. Also, endocrinopathies such as thyroid disease and metabolic syndrome represent relevant comorbidities but were not included in the study.

However, to the best of our knowledge, this is the first large-scale cohort study to address comorbidities with risk factors and monitoring status of RA patients in Korea. The current findings on the prevalence of comorbidities and risk factors in Korea will be helpful to rheumatologists in other Asian and non-Asian countries with similar situations.

In summary, the prevalence of CV morbidity was similar between patients in Korea and those in other countries, although the prevalence of CV risk factors is significantly low in Korea. Prostate cancer screening was less frequently performed compared to other countries and <10% of Korean RA patients were given both influenza and a pneumococcal vaccination according to current recommendations. Bone densitometry was more frequently done but vitamin D supplements were taken less in Korea compared to the international cohort. This suggests that rheumatologists in Korea need to pay more attention to yearly CV risk monitoring, in addition to the screening of malignancy, vitamin D supplements and vaccination of RA patients against infectious diseases.

ACKNOWLEDGEMENTS

The authors would like to thank the national princi- pal investigators of the COMORA study: Gustavo Casado (Argentina), Josef Smolen (Austria), Bassel Kamal El-Zorkany (Egypt), Martin Soubrier (France), Gerd Burmester (Germany), Peter Balint (Hungary), Carlo Maurizio Montecucco (Italy), Masayoshi Harigai (Japan), Najia Hajjaj-Hassouni (Morocco), Mart van de Laar (the Netherlands), Emilio Martin-Mola (Spain), Shue-Fen Luo (Taiwan), Jonathan Kay and Kevin Winthrop (USA), Gabriel Maciel (Uruguay), Anna Antunez (Venezuela); and the scientific committee of the COMORA study who permitted and supported this ancillary analysis: Maxime Dougados, Peter Balint, Gerd Burmester, Paul Emery, Jonathan Kay, Emilio Mar- tin-Mola, Iain McInnes, Carlo Maurizio Montecucco, Josef Smolen, and patients who agreed to participate in this study.

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FUNDING

Data collection was supported by an unrestricted grant from Roche. The ancillary study described in this manuscript was conducted with the support of a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1277) and by a grant from the Ministry of Science, ICT and Future Planning (NRF-2015M3A9B6052011).

DISCLOSURES

The authors have no conflicts of interest to declare.

AUTHOR CONTRIBUTION

Each author’s contribution to the paper is to be quanti- fied. IAC participated in patient enrollment and data analysis and wrote a manuscript. SHP, H-SC, WP, HAK, DHY, HJB, SGL, YJL, YBP, SCS and YWS are the princi- ple investigators of 11 Korean centers. IH managed and provided the international-COMORA data.

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