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1 Journal of Rheumatic Diseases Vol. 23, No. 1, February, Original Article 한국인류마티스관절염과골관절염환자의위장관위험인자와비스테로이드항염제사용비교 이은영 1 ㆍ홍승재 2 ㆍ박용범 3 ㆍ박경수 4 ㆍ최찬범 5 ㆍ이창근 6 ㆍ송란 7 ㆍ이윤종 8 ㆍ서창희 9 ㆍ김현아 10, 민준기 11 ㆍ윤종현 12 ㆍ박원 13 ㆍ정원태 14 ㆍ김근태 15 ㆍ최정윤 16 ㆍ강성욱 17 ㆍ박용욱 18 ㆍ류완희 19, 이상헌 20 1 서울대학교의과대학내과학교실류마티스내과, 2 경희의료원류마티스내과, 3 연세대학교의과대학세브란스병원내과학교실류마티스내과, 4 가톨릭대학교성빈센트병원류마티스내과, 5 한양대학교류마티스병원류마티스내과, 6 울산대학교의과대학서울아산병원내과학교실류마티스내과, 7 강동경희대학교병원류마티스내과, 8 분당서울대학교병원류마티스내과, 9 아주대학교병원류마티스내과, 10 한림대학교성심병원류마티스내과, 11 가톨릭대학교부천성모병원류마티스내과, 12 가톨릭대학교의정부성모병원류마티스내과, 13 인하대학교의과대학내과학교실류마티스내과, 14 동아대학교병원류마티스내과, 15 고신대학교복음병원류마티스내과, 16 대구가톨릭대학교의과대학내과학교실류마티스내과, 17 충남대학교의학전문대학원내과학교실, 18 전남대학교의과대학류마티스내과학교실, 19 전북대학교의학전문대학원내과학교실류마티스내과, 20 건국대학교병원류마티스내과 Gastrointestinal Risk Factors and Non-steroidal Anti-inflammatory Drugs Use in Rheumatoid Arthritis and Osteoarthritis Patients in Korea Eun Young Lee 1, Seung-Jae Hong 2, Yong-Beom Park 3, Kyung-Su Park 4, Chan-Bum Choi 5, Chang-Keun Lee 6, Ran Song 7, Yun Jong Lee 8, Chang Hee Suh 9, Hyun Ah Kim 10, Jun Ki Min 11, Chong-Hyeon Yoon 12, Won Park 13, Won Tae Chung 14, Geun-Tae Kim 15, Jung-Yoon Choe 16, Seong Wook Kang 17, Yong-Wook Park 18, Wan-Hee Yoo 19, Sang-Heon Lee 20 1 Division of Rheumatology, Seoul National University College of Medicine, Seoul, 2 Department of Rheumatology, Kyung Hee University Medical Center, Seoul, 3 Division of Rheumatology, Severance Hospital, Yonsei University College of Medicine, Seoul, 4 Department of Rheumatology, The Catholic University of Korea, St. Vincent's Hospital, Suwon, 5 Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, 6 Division of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 7 Department of Rheumatology, Kyung Hee University Hospital at Gangdong, Seoul, 8 Department of Rheumatology, Seoul National University Bundang Hospital, Seongnam, 9 Department of Rheumatology, Ajou University Hospital, Suwon, 10 Department of Rheumatology, Hallym University Sacred Heart Hospital, Anyang, 11 Department of Rheumatology, The Catholic University of Korea, Bucheon St. Mary's Hospital, Bucheon, 12 Department of Rheumatology, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, Uijeongbu, 13 Division of Rheumatology, Inha University School of Medicine, Incheon, 14 Department of Rheumatology, Dong-A University Hospital, Busan, 15 Division of of Rheumatology, Kosin University Gospel Hospital, Busan, 16 Division of Rheumatology, Catholic University of Daegu School of Medicine, Daegu, 17 Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 18 Department of Rheumatology, Chonnam National University Medical School, Gwangju, 19 Division of Rheumatology, Chonbuk National University Medical School, Jeonju, 20 Department of Rheumatology, Konkuk University Medical Center, Seoul, Korea Objective. The aim of this study was to examine and compare the gastrointestinal (GI) risk factors and treatment patterns of rheumatoid arthritis (RA) and osteoarthritis (OA) patients in Korea. Methods. This was a cross-sectional, observational study on RA and OA patients taking non-steroidal anti-inflammatory drugs (NSAIDs) for at least 1 month. A total of 1,896 patients (981 RA patients, 915 OA patients) were recruited from 20 university hospitals. Data were collected through medical records and patient Received:October 6, 2015, Revised:(1st) November 30, 2015, (2nd) January 21, 2016, Accepted:January 30, 2016 Corresponding to:sang-heon Lee, Department of Rheumatology, Konkuk University Medical Center, Neungdong-ro, Gwangjin-ju, Seoul 05030, Korea. shlee@kuh.ac.kr pissn: X, eissn: Copyright c 2016 by The Korean College of Rheumatology. All rights reserved. This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited. 47

2 Eun Young Lee et al. surveys. GI risk factors included age, prolonged (over 3 months) or high-dose use of NSAIDs, alcohol drinking, smoking, use of aspirin, anticoagulants or glucocorticoids, comorbidities, and history of Helicobacter pylori infection or other GI complications. Treatment patterns were classified according to groups using, selective cyclooxygenase (COX)-2 inhibitors±gastro-protective agents, non-selective COX-2 inhibitors+proton pump inhibitor, or non-selective COX-2 inhibitors±other gastro-protective agents. Results. GI risk factors were highly present in both RA and OA patients. The proportion of prolonged use of NSAIDs, smoking, and glucocorticoid use were higher in RA patients (p<0.001). The proportion of comorbidities and use of aspirin were higher in OA patients (p<0.001). The remaining GI risk factors were present in similar proportions in both groups. Use of selective COX-2 inhibitors or gastro-protective agents was higher in RA patients. Conclusion. Prolonged use of NSAIDs and concomitant glucocorticoid use were higher in RA patients, while comorbidities and concomitant aspirin use were predominant in OA patients. These results will provide insights for use in development of future guidelines for proper selection of NSAIDs and effective prevention of GI complications in arthritis patients. (J Rheum Dis 2016;23:47-54) Key Words. Rheumatoid arthritis, Osteoarthritis, Gastrointestinal risk factors, Non-steroidal anti-inflammatory agents 서론 비스테로이드항염제의사용은출혈, 궤양, 소화불량등의위장관계합병증을유의하게증가시키는것으로알려져있다 [1]. 이런부작용들은환자의삶의질, 질병이환율및사망률에중요한임상적영향을미치며, 의료비지출에도많은영향을미친다. 비스테로이드항염제로인한위장관계부작용때문에발생하는비용을조사한해외연구결과, 비스테로이드항염제에 1달러를소비시위장관계부작용에는 달러가소비되었다 [2,3]. 또한관절염환자들의총의료비용중약 33% 정도가위장관계부작용치료와관련되어있다는연구결과도발표되었다 [4]. 비스테로이드항염제로인한위장관계부작용을최소화하기위한방안으로는 misoprostol이나 proton pump inhibitors (PPIs) 를보조제로추가하거나선택적 cyclooxygenase (COX)-2 억제제를사용할것이권장되고있다. 비스테로이드항염제를복용중인환자들의기저위험요인을측정하여이런보호요법의대상환자를알아내는것은위장관계합병증발생률을낮출수있을것으로기대되지만, 진료현장에서상당한비율의고위험군환자에서이러한보호요법이시행되지않고있다는결과들이있다 [5-9]. 본연구에서는비스테로이드항염제를복용하는국내류마티스관절염및골관절염환자들을대상으로위장관계위험인자와실제비스테로이드항염제처방패턴및위장관보호제의사용을조사, 비교하였다. 대상및방법 본연구는비개입적, 다기관참여, 단면적관찰연구로 2012년 12월부터 2013년 9월까지국내 20개기관에서시행되었으며전기관의연구윤리심의위원회로부터승인을받았다. 조사대상은각의료기관에서연구대상자선정기준을만족하는류마티스관절염또는골관절염환자들을 대상으로하였다. 연구대상자의선정기준은만 20세이상, 류마티스관절염또는골관절염을진단받은경우, 연구참여당시비스테로이드항염제를적어도 1개월이상복용중인경우, 그리고서면동의설명문및동의서를이해할수있고제출할의사가있는경우로하였다. 류마티스관절염과골관절염이외의다른관절염을진단받은경우, 연구참여를부적절하게할수있는중증의급성또는만성의학적상태나정신상태를가진경우는제외되었다. 의무기록검토를통해연구대상자의위장관계위험인자, 인구학적기초자료, 임상특성, 비스테로이드항염제및위장관보호제처방패턴을수집하였다. 위장관계위험인자는비스테로이드항염제복용기간이 3개월이상, 권장용량이상의고용량비선택적비스테로이드항염제복용, 음주, 흡연, 기저질환 ( 순환기계, 내분비계, 호흡기계, 신장및간질환 ), 아스피린복용, 항응고제복용, 글루코코르티코이드복용, 헬리코박터파이로리감염력, 위장관출혈이나위궤양등의위장관계문제경험의열가지로정의하였다. 치료패턴은선택적 COX-2 억제제복용 ± 위장관보호제복용군 (PPI 복용군포함 ), 비선택적비스테로이드항염제 +PPI 복용군, 비선택적비스테로이드항염제 ± 기타위장관보호제복용군으로나누어분류하였다. 기타위장관보호제는 PPI를제외한 H2 수용체길항제, rebamipide, 제산제등을포함하였다. 류마티스관절염환자와골관절염환자의일반적특성과위장관계위험인자의보유여부에대한현황을평균및빈도 (%) 를통해알아보고, 그차이를확인하고자카이제곱검정을실시하였다. 또한연령별위험인자보유현황을 60 세기준으로확인하고 10세단위로각환자군에서확인하였다. 치료패턴은본연구의자료수집당시의요양급여기준에영향을받았을것이므로, 2012년당시급여제한이있던 65세를기준으로분류하여류마티스관절염환자군과골관절염환자군에서치료패턴차이를확인하고, 위장관계위험인자개수증가에따른치료패턴차이를카이제 48 J Rheum Dis Vol. 23, No. 1, February, 2016

3 GI risk factors of RA and OA 곱검정을이용하여확인하였다. 자료분석은통계프로그램 IBM SPSS Statistics ver (IBM Co., Armonk, NY, USA) 을이용하였고, 통계분석에서얻어진모든 p-value는양측검정의결과로, 통계적유의수준을 p=0.05를기준으로하였다. Table 1. Characteristics of rheumatoid arthritis and osteoarthritis patients Variable 결 과 총 1,896명의연구대상자가조사에참여하였고, 이중류마티스관절염은 981명 (51.7%), 골관절염은 915명 (48.3%) 이었다. Table 1은연구에포함된대상자들의일반적인특성을나타낸것이다. 대부분의환자가여자였으나, 류마티스관절염환자에서골관절염환자에비해남자의비율이높고 (14.9% vs. 9.0%, p<0.001), 평균나이가적었으며 (55.0±11.7 vs. 62.9±9.2 yr, p<0.001), 질환유병기간이길었다 (73.0±68.8 vs. 49.9±50.7 mo, p<0.001). 환자군을 60세미만과 60세이상으로나누었을때, 류마티스관절염환자군은각각 623명, 358명이었고, 골관절염환자군은각각 349명, 566명이었다. 65세미만과 65세이상으로나누었을때에는류마티스관절염환자군은각각 760 명, 221명이었으며, 골관절염환자군은각각 510명, 405 명이었다. Figure 1은류마티스관절염과골관절염환자들에서위장관계위험인자여부에차이가있는지를보여주는것이다. 위장관계위험인자는류마티스관절염환자와골관절염환자모두에서 90% 이상보유하고있는것으로나타났다. 특히류마티스관절염환자에서비스테로이드항염제의복용기간이 3개월이상인경우가더많았고, 흡연력이높았고, 글루코코르티코이드복용률이높았다. 골관절염환자에서기저질환, 특히순환기계질환과내분비계질환의동 Rheumatoid arthritis (n=981) Osteoarthritis (n=915) Age (yr)* 55.0± ±9.2 < (63.5) 349 (38.1) (36.5) 566 (61.9) < (77.5) 510 (55.7) (22.5) 405 (44.3) Sex* Male 146 (14.9) 82 (9.0) Female 835 (85.1) 833 (91.0) Disease duration (mo)* 73.0± ±50.7 Median (IQR) 55 (22 104) 33 (11 72) Range Values are presented as mean±standard deviation or number (%). IQR: interquartile range. *p<0.001 by chi-square test. 반률이높았고 ( 순환기계질환 32.4% vs. 47.9%, 내분비계질환 8.4% vs. 13.7%), 아스피린복용률이높았다 (Figure 1A). 이러한위장관계위험인자를가지고있는지의양상은 60세를기준으로나누어보았을때도비슷하였다. 60 세미만인환자그룹에서도 60세이상인환자그룹에서와비슷하게위장관계위험인자를가지고있는것으로관찰되었다. 특히고용량의비스테로이드항염제복용, 음주력, 흡연, 그리고글루코코르티코이드복용에있어서는 60세미만의환자군에서그비율이더높았다. 10세단위의연령별로위장관계위험인자보유분포에서도젊은연령층부터높은유병률을보이는위장관계위험인자들 ( 비스테로이드항염제복용기간이 3개월이상, 권장용량이상의고용량비선택적비스테로이드항염제복용, 음주등 ) 이있었으며전반적으로연령대와상관없이비슷한비율로가지고있음을알수있었다 (Figure 2). 전체환자에서비스테로이드항염제혹은선택적 COX-2 억제제의단독투여군의비율은각각 6.1% ( 비선택적비스테로이드항염제단독복용환자군 ), 7.2% ( 선택적 COX-2 억제제단독복용환자군 ) 으로매우적은것으로나타나, 이를고려하여치료패턴을 3그룹 ( 선택적 COX-2 억제제복용 ± 위장관보호제복용군, 비선택적비스테로이드항염제 +PPI 복용군, 비선택적비스테로이드항염제 ± 기타위장관보호제복용군 ) 으로분류하여분석하였다. 전체환자에서류마티스관절염환자군은선택적 COX-2 억제제를사용하는경우가 54.3% 로비선택적비스테로이드항염제를사용하는경우보다많았고, 골관절염환자군은비선택적비스테로이드항염제를사용하는경우가 55.8% 로선택적 COX-2 억제제를사용하는경우보다많았다 (p<0.001). 각각의질환군에서 65세를기준으로비스테로이드항염제및위장관보호제처방패턴을살펴보면, 65세이상인경우적절한위장관보호제사용군 ( 선택적 COX-2 억제제복용 ± 위장관보호제복용군과비선택적비스테로이드항염제 +PPI 복용군 ) 이 65세미만일때보다각군에서많았다 ( 류마티스관절염 77.3% vs. 66.6%, p=0.005; 골관절염 71.6% vs. 55.5%, p<0.001). 그러나 65세이상이라하더라도류마티스관절염환자들의 22.6% 와골관절염환자들의 28.4% 는적절한위장관계합병증예방치료가되고있지않음을보여주고있다 (Figure 3). 연령별두질환군의치료패턴차이는 65세미만에서는골관절염환자군에서류마티스관절염환자보다비선택적비스테로이드항염제단독이나 PPI 이외의다른위장관보호제와의병용사용이많았으나 (p<0.001), 65세이상에서는두질환군간차이가없었다 (Figure 3). Figure 4는류마티스관절염과골관절염환자들이가지고있는위장관계위험인자개수에따른비스테로이드항염제및위장관보호제처방패턴의차이를조사한것이다. 환자가보유한위장관계위험인자들의개수를 2개이하, 3 4개, 5개이상으로나누어치료패턴을살펴본결과, 두질 49

4 Eun Young Lee et al. Figure 1. Gastrointestinal (GI) risk factors in rheumatoid arthritis and osteoarthritis patients (A: all age, B: <60 yr, C: 60 yr). NSAID: non-steroidal anti-inflammatory drug. *p<0.001 by chi-square test. 환군모두에서갖고있는위장관계위험인자개수가증가함에도선택적 COX-2 억제제의사용빈도는증가하지않았고, 비선택적비스테로이드항염제 +PPI 사용비율이증가하는경향을보였으나, 적절한위장관예방치료가시행되지않는군 ( 비선택적비스테로이드항염제 ± 기타위장관보호제복용군 ) 이여전히 30% 이상존재함을확인할수있었다 (p<0.001). 두질환군간치료패턴의차이는골관 절염환자군에서류마티스관절염환자군에서보다적절한위장관예방치료 ( 비선택적비스테로이드항염제 ± 기타위장관보호제복용군 ) 가적게사용되는경향이있었다 (Figure 4). 50 J Rheum Dis Vol. 23, No. 1, February, 2016

GI risk factors of RA and OA Figure 2. Gastrointestinal (GI) risk factors stratified by 10 years age in rheumatoid arthritis and osteoarthritis patients (A: Rheumatoid arthritis, B: Osteoarthritis).

고찰 위장관계합병증과관련된다양한위험인자들은이미여러연구들을통해밝혀졌는데, 현재건강상태 [10,11], 고령 [12], 글루코코르티코이드병용 [13], 항응고제병용 [14], 위장관출혈경험 [15], 류마티스관절염 [16], 특정비스테로이드항염제사용경험 [17], 심혈관계기왕력 [18] 흡연 [10,19], 비스테로이드항염제에의한위장관증상 [11,14,20]

5 GI risk factors of RA and OA Figure 2. Gastrointestinal (GI) risk factors stratified by 10 years age in rheumatoid arthritis and osteoarthritis patients (A: Rheumatoid arthritis, B: Osteoarthritis). NSAID: non-steroidal antiinflammatory drug. 고찰 위장관계합병증과관련된다양한위험인자들은이미여러연구들을통해밝혀졌는데, 현재건강상태 [10,11], 고령 [12], 글루코코르티코이드병용 [13], 항응고제병용 [14], 위장관출혈경험 [15], 류마티스관절염 [16], 특정비스테로이드항염제사용경험 [17], 심혈관계기왕력 [18] 흡연 [10,19], 비스테로이드항염제에의한위장관증상 [11,14,20] 등이다. 따라서의료진은비스테로이드항염제를처방하기에앞서이런환자의임상적요인들을고려하여개개인의위험요인에맞는적절한치료를시행하는것이바람직하다. 국내정형외과연구진들이골관절염환자들을대상으로 조사한바에따르면, 위장관계고위험또는초고위험군에속하는환자는전체환자의 45% 에달하였지만, 이중에서선택적 COX-2 억제제를복용중인환자는 51% 에불과했다고보고하였다 [21]. 국외연구결과로스페인에서실시된골관절염환자를대상의대규모관찰연구에서도연구대상자의 90% 가넘는환자들이위장관계위험인자를보유하고있었으나, 이중 50% 가넘는환자들이당시의비스테로이드항염제처방지침이나권고사항에따라적절한치료를받지못한것으로보고되었다 [22]. 본연구에서도대다수의환자가위장관계위험인자를보유하고있음에도불구하고, 선택적 COX-2 억제제치료는연구대상자의절반정도에그쳐기존의국내외연구와비슷한경향을나타냈다. 이는국내에서아직도비스테로이드항염제로인한 51

6 Eun Young Lee et al. Figure 3. Treatment patterns of NSAIDs by age. Values are presented as percent only. COX-2i: selective cycloxygenase-2 inhibitor, ns-nsaid: non-selective non-steroidal anti-inflammatory drug, PPI: proton pump inhibitor. a vs. c, p<0.001; b vs. d, p= Figure 4. Treatment patterns in terms of gastrointestinal risk factor numbers. Values are presented as percent only. COX-2i: selective cycloxygenase-2 inhibitor, ns-nsaid: non-selective non-steroidal anti-inflammatory drug, PPI: proton pump inhibitor. a vs. d, p=0.046; b vs. e, p<0.001; c vs. f, p= 위장관계부작용을예방하기위한치료요법이적극적으로활용되고있지않음을보여주는결과이며, 이중일부는 PPI와선택적 COX-2 억제제사용에대한제한된급여기준에기인했을것으로사료된다. 연구자료가수집될당시국내급여기준에따르면선택적 COX-2 억제제는 65세이상의고령인경우, 상부위장관의궤양, 출혈및천공의치료기왕력이확인되는경우, 글루코코르티코이드를투여중인경우, 항응고제투여가필요한경우, 기존의비선택적비스테로이드항염제에불응성인경우, 대량의비선택적비스테로이드항염제를필요로하는경우에만요양급여를인정받았다. 이러한제한된급여기준으로인해당시에비선택적비스테로이드항염제투여로인한위장관부작용발생위험이높은 65세미만의환자들에대한보험급여인정이고려되지않았다. 2013년 7월에급여기준이개선되어 60세이상의고령자의경우도급여대상으로추가되었으나, 본연구에서확인된바와같이 60세미만의환자라고할지라도대다수의환자가위장관계질환발생의위험인자를보유하고있는것으로확인되었으므로더욱포괄적인급여기준이비용경제성연구를통해향후마련되어야할것으로생각된다. 특히비선택적비스테로이드항염제의사용은류마티스관절염환자보다골관절염환자에서더욱많은데, 이는골관절염환자가류마티스관절염환자에비해위장관계위험인자가낮을것이라는인식이존재하며, 골관절염환자의연령이류마티스관절염보다는비교적높아동반된심혈관질환이동반될가능성이높고이로인해선택적 COX-2 억제제사용을기피했을 가능성이높다. Laine 등 [23] 이시행한연구에서통계적으로는유의하지않지만, 골관절염환자가류마티스관절염환자보다복잡성상부위장관합병증발생률이 1.7배더높게나타남을보여주었다. 본연구의결과에따르면, 류마티스관절염환자에서비스테로이드항염제의복용기간이 3개월이상인경우가더많았으며, 흡연력이높았고, 글루코코르티코이드복용률이높았다. 반면골관절염환자에서는평균나이가높고, 기저질환, 특히순환기계질환과내분비계질환의동반률이높았으며, 아스피린복용률이높음을보여주었다. 질환에따라위장관계위험인자의분포가차이가날수는있으나, 골관절염이류마티스관절염보다위장관계합병증발생위험인자가낮다고할수는없다. 또한이러한양상은 60세미만인환자그룹에서도비슷하였고심지어 60세미만인환자군에서는 60세이상의환자군보다위장관계위험인자보유비율이더높은경우 ( 고용량의비스테로이드항염제복용, 음주력, 글루코코르티코이드복용 ) 도관찰되었다. 따라서 60세미만젊은연령의류마티스관절염혹은골관절염환자라고할지라도비스테로이드항염제복용시위장관계위험인자의고려가반드시필요하다. 본연구는국내 20개기관에서대규모의류마티스관절염환자와골관절염환자를대상으로비스테로이드항염제 / 위장관보호제의사용패턴과위장관계위험인자들을같이조사함으로써, 어떠한개입도없이실제진료현장에서이루어지고있는처방의형태와요인들을수집하여분석하였다는데큰의의를둘수있을것으로생각된다. 결과 52 J Rheum Dis Vol. 23, No. 1, February, 2016

7 GI risk factors of RA and OA 적으로실제진료현장에서관절염환자들에게비스테로이드항염제를비교적장기간사용하는경우에위장관계위험인자들이다소과소평가될우려가있음을보여주었고, 위장관계위험인자들을보다쉽게가려낼수있는평가도구가필요함을시사하는결과라고할수있겠다. 본연구의제한점으로단면적관찰연구로인해, 조사된위험인자들이실제위장관계합병증에어떠한영향을미치는지를관찰하지못한점, 위험인자의종류, 누적개수에따른처방패턴에미치는영향을충분히분석할수없는한계점을들수있다. 그러나국내 20개기관에서 2,000명에달하는대규모의환자들을대상으로류마티스관절염과골관절염환자들이가지고있는위장관계위험인자들과함께실제비스테로이드항염제처방의형태를보여주어, 향후연구나처방권고수립에유용한자료가될수있겠다. 결 론 류마티스관절염환자와골관절염환자모두위장관계위험인자를가지고있지만, 개별적인위험인자의분포는서로차이점을보였다. 특히비스테로이드항염제의종류및위장관보호제의사용빈도에서도두질환간에차이를보여향후관절염환자에서비스테로이드항염제의선택과위장관합병증예방을위한가이드라인을제시하는데기초자료가될것으로기대한다. CONFLICT OF INTEREST This study was sponsored by Pfizer Pharmaceutical Korea Ltd. REFERENCES 1. Laine L. GI risk and risk factors of NSAIDs. J Cardiovasc Pharmacol 2006;47 Suppl 1:S Rahme E, Joseph L, Kong SX, Watson DJ, LeLorier J. Gastrointestinal health care resource use and costs associated with nonsteroidal antiinflammatory drugs versus acetaminophen: retrospective cohort study of an elderly population. Arthritis Rheum 2000;43: Smalley WE, Griffin MR, Fought RL, Ray WA. Excess costs from gastrointestinal disease associated with nonsteroidal anti-inflammatory drugs. J Gen Intern Med 1996;11: Bloom BS. Direct medical costs of disease and gastrointestinal side effects during treatment for arthritis. Am J Med 1988;84(2A): American Gastroenterological Association, Wilcox CM, Allison J, Benzuly K, Borum M, Cryer B, et al. Consensus development conference on the use of nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 enzyme inhibitors and aspirin. Clin Gastroenterol Hepatol 2006;4: Rostom A, Moayyedi P, Hunt R; Canadian Association of Gastroenterology Consensus Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 2009;29: Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009;104: Abraham NS, El-Serag HB, Johnson ML, Hartman C, Richardson P, Ray WA, et al. National adherence to evidence-based guidelines for the prescription of nonsteroidal anti-inflammatory drugs. Gastroenterology 2005;129: Laine L, Connors L, Griffin MR, Curtis SP, Kaur A, Cannon CP. Prescription rates of protective co-therapy for NSAID users at high GI risk and results of attempts to improve adherence to guidelines. Aliment Pharmacol Ther 2009;30: Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl 1999;56: Fries JF. NSAID GI toxicity: epidemiology. J Musculoskel Med 1991;8: Fries JF, Williams CA, Bloch DA, Michel BA. Nonsteroidal anti-inflammatory drug-associated gastropathy: incidence and risk factor models. Am J Med 1991;91: Piper JM, Ray WA, Daugherty JR, Griffin MR. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med 1991;114: Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993;153: Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991;115: Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol Suppl 1998;51: Gutthann SP, García Rodríguez LA, Raiford DS. Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation. Epidemiology 1997;8: Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123: McIntosh JH, Fung CS, Berry G, Piper DW. Smoking, nonsteroidal anti-inflammatory drugs, and acetaminophen in gastric ulcer. A study of associations and of the effects of previous diagnosis on exposure patterns. Am J Epidemiol 1988;128: Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 1998;105:31S-8S. 21. Lee SH, Han CD, Yang IH, Ha CW. Prescription pattern of NSAIDs and the prevalence of NSAID-induced gastro- 53

8 Eun Young Lee et al. intestinal risk factors of orthopaedic patients in clinical practice in Korea. J Korean Med Sci 2011;26: Lanas A, Garcia-Tell G, Armada B, Oteo-Alvaro A. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis. BMC Med 2011;9: Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP. Risk factors for NSAID-associated upper GI clinical events in a longterm prospective study of arthritis patients. Aliment Pharmacol Ther 2010;32: J Rheum Dis Vol. 23, No. 1, February, 2016

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R