Korean Observational Study Network for Arthritis (KORONA): Establishment of a Prospective Multicenter Cohort for Rheumatoid Arthritis in South Korea

RHEUMATOID ARTHRITIS

Korean Observational Study Network for Arthritis (KORONA): Establishment of a Prospective Multicenter Cohort for Rheumatoid Arthritis in South Korea Yoon-Kyoung Sung, MD, PhD, MPH,*,† Soo-Kyung Cho, MD, PhD,*,† Chan-Bum Choi, MD, PhD,*,† So-Yeon Park, MD,*,† Jeeseon Shim, PhD,*,† Joong Kyong Ahn, MD, PhD,‡ So-Young Bang, MD, PhD,§ Hoon-Suk Cha, MD, PhD,‡ Jung-Yoon Choe, MD, PhD,储 Won Tae Chung, MD, PhD,¶ Minyoung Her, MD,** Seung-Jae Hong, MD, PhD,†† Yun Kyung Hong, MD, PhD,‡‡ Chung-Il Joung, MD, PhD,§§ Jae-Bum Jun, MD, PhD,* Young Ok Jung, MD, PhD,储储 Young Mo Kang, MD, PhD,¶¶ Dong-Yook Kim, MD, PhD,** Hae-Rim Kim, MD, PhD,*** Hyoun Ah Kim, MD, PhD,††† Jinseok Kim, MD, PhD,‡‡‡ Seong-Kyu Kim, MD, PhD,储 Sung-Il Kim, MD, PhD,§§§ Tae-Hwan Kim, MD, PhD,* Tae-Jong Kim, MD, PhD,储储储 Eunmi Koh, MD, PhD,‡ Choong Ki Lee, MD, PhD,¶¶¶ Hye-Soon Lee, MD, PhD,§ Jisoo Lee, MD, PhD,**** Sang-Heon Lee, MD, PhD,*** Sang-Hoon Lee, MD, PhD,†††† Shin-Seok Lee, MD, PhD,储储储 Sung Won Lee, MD, PhD,¶ Yeon-Ah Lee, MD, PhD,†† Seong-Su Nah, MD, PhD,‡‡‡‡ Sung-Hoon Park, MD, PhD,储 Dong Hyuk Sheen, MD, PhD,§§§§ Seung-Cheol Shim, MD, PhD,§§§§ Gwan Gyu Song, MD, PhD,储储储储 Chang-Hee Suh, MD, PhD,††† Wan-Sik Uhm, MD, PhD,* Dae-Hyun Yoo, MD, PhD,* Wan-Hee Yoo, MD, PhD,‡‡ Bo Young Yoon, MD, PhD,¶¶¶¶ and Sang-Cheol Bae, MD, PhD, MPH*,†

Objectives: The object of this study was to introduce the KORean Observational study Network for Arthritis (KORONA) registry with an emphasis on the design of the Korean rheumatoid arthritis (RA) national database, as well as to provide an overview of the RA patients who are currently registered in KORONA. Methods: The KORONA was established in July 2009 by the Clinical Research Center for Rheumatoid Arthritis (CRCRA) in South Korea. KORONA is based on a prospective protocol and standard, defined data collection instruments. Demographic and clinical features, laboratory and radiologic data, health-related outcomes, treatment side effects, resource utilization, and health behaviors of the RA cohort patients are recorded in a database. Results: A total of 23 institutions, which are about 38% of the rheumatologic departments at tertiary academic hospitals across South Korea, are part of KORONA. The quality control of data collection and management has been performed through annual monitoring and auditing, staff training, and providing standard operation protocol by the executive committee of CRCRA. As of 31 December 2010, 4721 patients with established RA were included in KORONA, because an annual survey had started to be performed in July 2010. 0049-0172/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2011.09.007

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Conclusions: KORONA is the first nationwide Korean RA-specific cohort and it will provide valuable “real-world” information for Korean RA patients. © 2012 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:745-751 Keywords: rheumatoid arthritis, cohort study, prospective study

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heumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects 0.5% to 1.0% of the adult population, making it the most common autoimmune rheumatic disease (1). It is characterized by symmetric inflammatory polyarthritis that causes joint deformity and progressive physical disability. In addition, daily pain, stiffness, and fatigue limit the activities of daily living. Management of RA aims to decrease active inflammation, prevent irreversible damage, and, ultimately, improve the quality of life (QOL) (2). It has now been established that early diagnosis, early intervention, and combination therapy with disease-modifying antirheumatic drugs (DMARDs) or biologics can prevent poor outcomes in RA patients (3). Recently, there has been an increase in awareness that clinical and laboratory markers do not capture the full experience of RA-associated disability or the associated decrease in QOL. The manner in which patients with RA cope with their daily pain and physical disability may affect their QOL. The personal, social, and economic resources to which the patient has access also influence their QOL and their health status. This has led to the establishment of a new prospective cohort in which to investigate the socio-economic consequences of living with RA.

A large, nationwide cohort of clinically well-characterized RA patients is a valuable resource for high-quality RA research (4,5). The KORean Observational study Network for Arthritis (KORONA) was established in July 2009 by the Clinical Research Center for Rheumatoid Arthritis (CRCRA), funded by the Ministry of Health and Welfare, South Korea. KORONA uses a prospective protocol and standard, defined data collection instruments. KORONA’s mission is to advance clinical research on RA and to improve the quality of care for RA patients in South Korea. KORONA has 2 major aims. The first is to gather high-quality data regarding RA disease outcomes such as QOL, treatment effectiveness, adverse effects, comorbidity, and disease progression. The second is to improve the quality of care for RA patients through standardization of patient assessments with nationwide communication between rheumatologists and to provide information to RA patients. The purpose of this article is to introduce the KORONA registry with an emphasis on the design of the Korean RA national database, as well as to provide an overview of the RA patients who are currently registered in KORONA. METHODS Organization and Funding Source

*Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea. †Clinical Research Center for Rheumatoid Arthritis (CRCRA), Seoul, South Korea. ‡Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea. §Hanyang University Guri Hospital, Guri, South Korea. 储Catholic University of Daegu School of Medicine, Daegu, South Korea. ¶Dong-A University Hospital, Busan, South Korea. **Inje University Pusan Paik Hospital, Busan, South Korea. ††Kyung Hee University Hospital, Seoul, South Korea. ‡‡Chonbuk National University Hospital, Jeonju, South Korea. §§Konyang University Hospital, Daejeon, South Korea. 储储Hallym University Kangnam Sacred Heart Hospital, Seoul, South Korea. ¶¶Kyungpook National University Hospital, Daegu, South Korea. ***Konkuk University Medical Center, Seoul, South Korea. †††Ajou University Hospital, Suwon, South Korea. ‡‡‡Jeju National University Hospital, Jeju, South Korea. §§§Pusan National University Hospital, Busan, South Korea. 储储储Chonnam National University Hospital, Gwangju, South Korea. ¶¶¶Yeungnam University Hospital, Daegu, South Korea. ****Ewha Womans University Mokdong Hospital, Seoul, South Korea. ††††Kyung Hee University Hospital at Gangdong, Seoul, South Korea. ‡‡‡‡Soonchunhyang University Cheonan Hospital, Cheonan, South Korea. §§§§Eulji University Hospital, Daejeon, South Korea. 储储储储Korea University Kuro Hospital, Seoul, South Korea. ¶¶¶¶Inje University Ilsan Paik Hospital, Goyang, South Korea. This study was supported by a grant from the Korea Health care Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065). Address reprint requests to Sang-Cheol Bae, MD, PhD, MPH, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea. E-mail: [email protected].

The KORONA was established in July 2009 by the CRCRA. The CRCRA has support from the Korean Ministry of Health and Welfare from November 2008 to March 2015 and is 1 of the major initiatives of the National Strategic Coordinating Center for Clinical Research, a nonprofit organization that deals with 11 high-impact diseases in South Korea. The mission of the CRCRA is to improve health outcomes and QOL for RA patients and to promote multidisciplinary RA clinical research across South Korea. Clinical research projects include registry- and population-based studies, biological sample banks, QOL and psychosocial research studies, health outcomes and health services research, investigator-initiated trials, clinical practice guidelines, biomarkers, and translational research. The main center of the CRCRA is located at Hanyang University Hospital for Rheumatic Diseases in Seoul, the largest rheumatology teaching hospital in South Korea. Ethical Considerations More than 40 academic rheumatologists from 23 teaching hospitals, which are about 38% of rheumatologic de-

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Figure 1 KORONA’s nationwide RA registry across South Korea. (Color version of figure is available online.)

partments at tertiary academic hospitals across South Korea, are part of the network, and the hospitals that were members of KORONA as of March 2011 are shown in Figure 1. KORONA has an independent steering committee that handles the regulatory, practical, and scientific aspects of the registry. KORONA is managed by the steering committee, and the research teams function independent of government control and pharmaceutical company involvement, although KORONA is financially supported by the government of South Korea. The KORONA protocol was approved by the institutional review boards of all participating hospitals, and informed consent was obtained from all patients before registration. This study is registered in the Clinical Research Information Service of South Korea (Board Approval Number KCT0000086), 1 of the primary registries in the WHO International Clinical Trials Registry Platform (http:// ncrc.cdc.go.kr/cris/index.jsp). The study was reported following the Strengthening the Reporting of Observational Studies in Epidemiology recommendations (6). Data Collection Standardized protocols for patient enrollment and data quality control are followed by all KORONA-participating hospitals. The initial sample size was calculated to detect major infection such as tuberculosis in the treatment of RA between biologic and nonbiologic DMARDs users. Patient Enrollment RA patients over the age of 18 who satisfied the 1987 American College of Rheumatology classification criteria

for RA and who planned to have their blood drawn for routine evaluation were recruited by rheumatologists in the different participating hospitals during their routine clinic visit as part of their usual care (Fig. 2). All patients are required to provide informed consent and to complete an initial questionnaire to establish their demographic profile, history, and disease-specific outcomes before enrollment. Disease activity is evaluated by a physician, whereas joint assessments are made by rheumatologists or well-trained health professionals certified by the CRCRA. Laboratory tests, prescription information, and patient self-evaluations are integrated into the KORONA database. Recruitment started in July 2009 and is due to be completed by March 2012. A total of 23 South Korean centers all across the South Korea are participating in this study and it ensures that a cohort of the full spectrum of patients with RA. Annual follow-up was initiated in July 2010. We contact the patients on the telephone at intervals of about 2 months, if the patients are lost to followup. The reasons are collected as data when patients do not want to participate at each stage. As of December 31, 2010, more than 95% of patients who were requested by each rheumatologist had consented to participate in the survey and a total of 4721 established RA patients had been included in KORONA. Data Entry and Feedback Data are collected on scannable paper forms, which are subsequently scanned into the database at the KORONA (CRCRA) office. Data entry is performed using scanning technology, which has eliminated hand coding and has reduced data entry time and delays in data entry, while

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Figure 2 Patient recruitment flow in KORONA.

increasing data standardization, quality, entry efficiency, and accuracy. The scanning coordinator and staff are trained in scanner operation, software usage, document preparation, and problem resolution. The scanning software performs coding and range and relationship checks and provides review for ambiguous entries, which are then corrected and exported into an EXCEL file. Within 2 months, data are returned to the rheumatologist as paper graphs showing changes over time in disease activity, functional disability, and laboratory data. All enrolled patients also receive health status feedback from the main center of KORONA. Data Sets Data are collected by means of interviews, self-administered questionnaires, and clinical examinations. Self-report questionnaires are administered in part during the

interview and in part directly after the interview. The data for each patient with RA consist of 2 components: events during the year of the study (hospitalization, surgery, malignancy, and tuberculosis) and information collected during their regular practice [number of tender and swollen joints, patient’s global and pain visual analog scale (VAS) scores, use of corticosteroids, DMARDs, and nonsteroidal anti-inflammatory drugs]. Variables in the KORONA registry are listed in Table 1. Demographic and clinical features. Demographic data collected include age, gender, lifestyle features (alcohol, smoking, exercise habits), marital and educational status, income, family structure, and socio-economic burden due to disease. Clinical information related to RA [disease duration, initial fulfillment of 1987 American College of Rheumatology (ACR) classification criteria for

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Table 1 Variables in the KORONA Registry Characteristic Demographic and clinical features Age, gender, and BMI Diagnostic code Year of diagnosis Initial fulfillment of 1987 ACR classification criteria Educational level Marital status and family type Family history Income Comorbidity Operation and hospitalization Reproductive history Tobacco use Alcohol consumption Alternative medicine use Vaccination history Previous DMARDs Current treatment Compliance Adverse effects of treatment Laboratory and radiological data RF status Anti-CCP status Inflammatory markers (ESR, CRP) Full blood count, LFT, RFT Chest radiograph Hand radiograph Bone mineral density (optional) Charlson comorbidity index Health-related outcomes Physician-assessed disease activity DAS 28 HAQ Pain VAS Patient’s GH VAS VAS for fatigue VAS for sleeping Physician’s GH VAS EQ-5D Biospecimens (Eight major centers only)

At At Annual Baseline Visit

test, and measurement of creatinine and electrolyte levels. Information from chest and hand radiographs, as well as bone mineral density data, is collected. outcomes. Disease Activity Score (DAS) in 28 joints (7), the responses to the Health Assessment Questionnaire (HAQ) (8), and the EuroQol 5 Dimensions (EQ-5D) (9) are used to assess health-related outcomes. VAS scores for physician’s global health (GH) assessment, patient’s pain, and GH assessment, VAS for fatigue, and VAS for sleeping are also collected.

Health-related Œ Œ Œ Œ

ΠX X X

Œ Œ Œ Œ Œ Œ Œ Œ Œ Œ X Œ Œ Œ Œ

X Œ Œ Œ Œ Œ Œ Œ Œ Œ Œ X Œ Œ Œ

ΠΠΠΠΠΠΠX

Œ Œ Œ Œ Œ Œ Œ Œ

X

Œ

Œ Œ Œ Œ Œ Œ Œ Œ Œ

Œ Œ Œ Œ Œ Œ Œ Œ Œ

RA, experience of adverse effects during RA treatment, surgery, bone fractures] and other general clinical information (prescriptions, hospitalizations within the previous 2 years, and comorbidity) are also obtained. Laboratory and radiological data. Laboratory data to

identify characteristics of RA [anti-cyclic-citrullinated protein (CCP) antibody, rheumatoid factor (RF)] are obtained, and disease activity is monitored using erythrocyte sedimentation rate (ESR) and C-reactive protein. Furthermore, possible side effects of drugs are evaluated by performing full blood counts, a liver function test, a urine

RESULTS A total of 4922 patients were enrolled in KORONA as of December 2010: 4721 consenting patients and 201 nonconsenting patients. The population of 4721 consenting patients had a mean age of 54.25 ⫾ 12.19 years and included 4023 women (85.21%). The mean symptom onset age was 43.89 ⫾ 12.99 years, and the mean disease duration was 8.30 ⫾ 7.57 years. RF positivity and antiCCP antibody positivity were 86.8% (4098/4719) and 83.9% (3018/3599), respectively. The comorbidities at enrollment are shown in Table 2. Hypertension was the most frequent concomitant disease, followed by gastrointestinal disease. In terms of treatment, 97.48% (4569/ 4687) of patients were taking DMARDs, and 271 (5.78%) patients were taking biologic agents. When patients were stratified according to their DAS in 28 joints, the percentages of patients in remission (⬍2.6) or with low RA activity (2.6ⱕ and ⬍3.2), moderate activity (3.2ⱕ and ⱕ5.1), or high activity (5.1⬍) were 20.97% (898/4239), 15.19% (644/4239), 46.87% (1987/4239), and 16.96% (719/4239), respectively. The mean HAQ score was 0.69 ⫾ 0.66 (from 0 to 3.00) and the mean EQ-5D score was 0.67 ⫾ 0.27 (from ⫺0.594 to 1.00). The HAQ and EQ-5D got worse with increasing disease activity. DISCUSSION Data on nearly 5000 patients were entered into the registry, until December 2010. KORONA has a number of features that deserve particular mention. First, efforts to ensure high-quality data collection and management have been made by the CRCRA. A major challenge with this study is to assure that the KORONA data and samples are of consistently high quality, especially given the large number of centers involved in the study. Several measures are used to ensure the consistency of the data and the quality of the samples. During the setup phase of the cohort, we held a series of meetings inviting all recruiting clinicians and health professionals to discuss all aspects concerning the recruitment process such as the design of the study database, patient identification and selection, the organization of recruitment, data and sample collec-

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Table 2 General Characteristics at Enrollment Total Number (%), Number mean ⫾ SD Demographic features Gender (female) Age (yr) Smoking status: Nonsmoker Smoking status: Current smoker Clinical features Onset age Disease duration (yr) Number of ACR classification criteria fulfilled ⬍4 Number of ACR classification criteria fulfilled ⱖ4 Rheumatoid factor positivity Anti-CCP antibody positivity Comorbidity at enrollment Cardiovascular disease Hypertension Respiratory disease Gastrointestinal disease Hepatic disease Renoureteral disease Diabetes Drug utilization DMARDs user Methotrexate DMARDs monotherapy DMARDs combination therapy NSAIDs user Steroids user Biologics user Health-related outcomes DAS28-ESR Remission (⬍2.6) Low activity (2.6ⱕ and ⬍3.2) Moderate activity (3.2ⱕ and ⱕ5.1) High activity (⬎5.1) Physician’s GH VAS Patient’s GH VAS Pain VAS HAQ Remission (DAS28 ⬍ 2.6) Low activity (2.6ⱕ DAS28 ⬍3.2) Moderate activity (3.2ⱕ DAS28 ⱕ5.1) High activity (DAS28 ⬎ 5.1) EQ-5D Remission (DAS28 ⬍ 2.6) Low activity (2.6ⱕ DAS28 ⬍3.2) Moderate activity (3.2ⱕ DAS28 ⱕ5.1) High activity (DAS28 ⬎5.1)

4721 4023 (85.21) 4720 54.25 ⫾ 12.19 4707 3962 (84.17) 377 (8.01) 4508 43.89 ⫾ 12.99 4574 8.30 ⫾ 7.57 4719 232 (4.9) 4487 (95.1) 4719 3599

4098 (86.8) 3018 (83.9)

4721 4721 4721 4721 4721 4721 4721

191 (4.05) 1204 (25.50) 412 (8.73) 993 (21.03) 231 (4.89) 124 (2.63) 384 (8.13)

4687 4687 4687 4687

4569 (97.48) 3814 (81.37) 1425 (30.40) 3144 (67.08)

4687 4687 4687

3798 (81.03) 3468 (73.99) 271 (5.78)

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3.75 ⫾ 1.37 888 (20.98) 640 (15.12) 1988 (46.98)

716 (16.92) 4693 27.02 ⫾ 19.29 4715 40.72 ⫾ 26.50 4716 38.05 ⫾ 28.36 4703 0.69 ⫾ 0.66 0.24 ⫾ 0.36 0.42 ⫾ 0.48 0.74 ⫾ 0.59 4707

1.34 ⫾ 0.70 0.67 ⫾ 0.27 0.83 ⫾ 0.17 0.76 ⫾ 0.19 0.66 ⫾ 0.22 0.43 ⫾ 0.34

tion, and strategies to secure research infrastructure support. Adequate training and support for staff recruitment are provided via group training meetings and 1-on-1 training during site visits. We also provide certificates to those who have completed the educational program for joint assessment on the standardization of swollen and tender joints. The formal, written manual and protocol for standard operation procedures has been drawn up. In addition, to ensure quality of data collection from medical record, we perform monitoring and auditing, and all data are checked for accuracy and completeness. A formal audit is also performed at least once a year in all KORONAparticipating hospitals. Second, to maximize the utilization of the cohort data and the KORONA resources for high-quality RA clinical research, annual research proposal meetings are held. The opportunity to propose new research ideas is available to anyone in the KORONA network, as well as other rheumatologists and researchers. All research proposals submitted by KORONA research teams are peer-reviewed by a referee committee. Authors selected through the original process are asked to present their research to all KORONA researchers. Third, CRCRA has also established the KOrean Registry of Biologics for Rheumatoid Arthritis, which focuses on the effectiveness and adverse effects of biologic agents in the treatment of RA. KOrean Registry of Biologics for Rheumatoid Arthritis includes 2 kinds of cohort studies: prospective and retrospective. A prospective inception cohort for biologic treatment of RA, the so-called Biologics Pharmacoepidemiologic Study, is scheduled to start in 2011. This cohort is based on the KORONA network and the retrospective cohort for biologics users, RESEARCh (Retrospective study for Safety and Effectiveness of Anti-Rheumatic treatment with biologiCs), which was started at Hanyang University Hospital for Rheumatic Diseases in 2010. These registries will need to be managed, coordinated, and ultimately connected to the KORONA database. Fourth, 8 major institutes that are KORONA participants are collecting blood samples from participants at each visit for genetic and biomarker studies of RA in South Korea. Another strength of KORONA is the potential for international collaboration, as it contains a large number of variables included in previous prospective cohorts conducted in Western countries and Japan (4,10,11). In the setup phase of the registry, we have reviewed the variables and management of Consortium of Rheumatology Researchers of North America (4). We also initiated communication with Japanese researchers at the Institute of Rheumatology Rheumatoid Arthritis at Tokyo Women’s Medical University, who evaluated the largest Japanese RA cohort (11) to establish a future comparison study between these 2 East Asian countries. KORONA is the first nationwide Korean RA-specific cohort that will provide valuable “real-world” information. The results from the KORONA study will poten-

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tially enhance RA clinical research and improve the quality of care for RA patients in South Korea. Moreover, it will allow comparative studies of RA between countries. REFERENCES 1. Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am 2001;27:269-82. 2. Whalley D, McKenna SP, de Jong Z, van der Heijde D. Quality of life in rheumatoid arthritis. Br J Rheumatol 1997;36:884-8. 3. Finckh A, Liang MH, van Herckenrode CM, de Pabol P. Longterm impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis. Arthritis Rheum 2006;55: 864-72. 4. Kremer J. The CORRONA database. Ann Rheum Dis 2005; 64(Suppl 4):iv37-41. 5. van der Woude D, Young A, Jayakumar K, Mertens BJ, Toes RE, van der Heijde D, et al. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum 2009;60:2262-71.

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