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1 Journal of Rheumatic Diseases Vol. 20, No. 6, December, Original Article TNF-α 길항제가적응이되는류마티스관절염환자들의임상양상 손경민ㆍ정영옥ㆍ김인제ㆍ김범준ㆍ이성연ㆍ문소영ㆍ서영일ㆍ김현아 한림대학교의과대학류마티스내과학교실 Clinical Characteristics of Korean Rheumatoid Arthritis Patients with Indications for TNF-α Blocker Kyeong Min Son, Young Ok Jung, In Je Kim, Bum Jun Kim, Seung Yun Lee, So Young Mun, Young Il Seo, Hyun Ah Kim Division of Rheumatology, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea Objective. The aim of this study was to examine clinical characteristics of Korean rheumatoid arthritis (RA) patients with clinically indications for TNF-α blocker, and to compare their clinical parameters with the Korean National Health Insurance reimbursement criteria. Methods. Data were obtained from a registry of RA patients who visited rheumatology clinics of Hallym University affiliated hospitals. Among patients who were previously prescribed DMARDs for more than three months, rheumatologists selected patients clinically indicated for TNF-a blocker. The clinical characteristics at the time TNF-α blocker use was deemed indicated were examined. Radiographic damage was quantified by Modified Sharp van der Heijde score in hand and foot simple AP radiograph. Results. From August 2010 to January 2013, five rheumatologists in four hospitals selected 109 patients clinically indicated for TNF-α blocker. When TNF-α blocker was considered, mean DAS28 was 5.2 (range ), mean swollen joint count was 6 (range 0 22), mean tender joint count was 10.6 (range 0 28), mean ESR was 43.2 mm/hr (range 1 140) and mean CRP was 2.5 mg/dl (range ). The mean total modified Sharp van der Heijde score was (range 0 240). Eighty one percent of subjects did not have enough active joints to satisfy the Korean National Health Insurance reimbursement standard. Conclusion. Our results show that patients with clinically indications for TNF-α blocker had a broad range of disease activity and clinical parameters, and the majority did not meet the Korean National Health Insurance reimbursement criteria Key Words. Rheumatoid arthritis, TNF-α blocker, Korean National Health Insurance reimbursement criteria 서론류마티스관절염은다관절에서발생하는만성적인자가면역성염증질환으로, 관절의파괴및기능저하를가져오며이로인하여일상생활의장애뿐아니라노동및경제적 손실을가져오게된다 (1). 1990년대후반부터도입된생물학적제제의개발은현재항류마티스약제 (DMARD) 에불충분한효과를보이는활동성류마티스관절염환자에게사용됨으로써많은경우에서좋은치료효과를보이고있 <Received:October 14, 2013, Revised:December 1, 2013, Accepted:December 4, 2013> Corresponding to:hyun Ah Kim, Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, 896, Pyongchon-dong, Dongan-gu, Anyang , Korea. kimha@hallym.ac.kr pissn: X, eissn: Copyright c 2013 by The Korean College of Rheumatology 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. 356

2 Korean RA Patients Indicated for TNF-α Blocker 357 다 (2-4). 하지만이러한생물학적제제는높은약제비및약물유해반응등을고려하여현재국내에서는보험기준을만족하는경우에한하여약제비의보험급여인정을하기때문에현실적으로는한국건강보험기준을만족하는경우에만사용이가능하다. 하지만미국, 영국, 일본류마티스학회 TNF-α 길항제사용가이드라인과한국의료보험급여기준비교조사연구에따르면, 다른나라의 TNF-α 길항제사용가이드라인을만족하는류마티스관절염환자중많은수에서한국의료보험급여기준을만족하지못하는것을알수있었다 (5). 그리하여본연구에서는실제임상에서류마티스전문의의판단하에 TNF-α 길항제의사용이고려되는환자의임상적특징및질환활성도를알아보고, 이들환자에서한국의료보험급여기준에대한충족여부를조사하고자하였다. 대상및방법 4개대학병원에서 1987년또는 2010년미국류마티스학회 (American College of Rheumatology, ACR) 진단기준에따라류마티스관절염을진단받고, 1번이상의 DAS28-ESR 을측정하였으며, 3개월이상항류마티스약제를처방받은환자들의의무기록을 2010년 8월에서 2013년 1월사이의기간동안후향적으로조사하였다. 의무기록을통하여환자의연령, 성별, 치료및질병이환기간, 사용중인항류마티스약제종류및스테로이드의사용여부및용량을조사하였다. 질병활성도평가는 DAS28-ESR을이용하였으며, 종창관절수 (swollen joint count, STC) 및압통관절수 (tender joint count, TJC), 활성관절수 (active joint count) 를측정하였다. 관절평가는 DAS28에포함된 28개의관절을평가하였다. 혈액검사에는류마티스인자 (rheumatoid factor, RF), 항CCP항체 (anti-cyclic citrullinated protein antibody, ACPA) 양성여부, 적혈구침강속도 (ESR), C-반응단백 (CRP) 을조사하였다. 또한 TNF-α 길항제의사용이고려되는시점의 1년내외에시행한수부및족부 X-ray를조사하였으며방사선학적정량검사는네덜란드의 Van der Heijde 교수팀에게의뢰하여 van der Heijde s modification of sharp s methods를사용하여분석하였다 (6). TNF-α 길항제의사용이고려되는환자는최소한 3개월이상 methotrexate를포함한 2가지이상의항류마티스약제를사용하였으나임상적호전이없거나, methotrexate를사용할수없는경우에는 methotrexate 이외의 2가지이상의항류마티스약제를사용한경우로정의하였다. TNF-α 길항제의사용고려여부는한림대학교의료원에근무하는 5명의류마티스내과전문의가임상적으로판단하였다. 한국의건강보험기준은조조강직이 45분이상, 활성관절수 ( 하나의관절내에종창및압통이같이관찰되는관절수 ) 가총 20개이상이거나또는 4개의대관절 ( 양어깨, 팔꿈치, 팔목, 무릎, 발목, 고관절 ) 을포함하여 6관절이상인경우, ESR 28 mm/hr 또는 CRP 2 mg/dl, 2종류이상의 항류마티스약제를각각 3 개월이상씩치료한경우이다 (7). 통계적처리는 SPSS 통계프로그램을이용하였고모든수치는평균 ± 표준편차로표시하였다. 결과 2010년 8월에서 2013년 1월사이의기간동안한림대학교의료원류마티스내과를방문하여 3개월이상항류마티스약제를처방받고 1번이상의 DAS28-ESR을측정한총대상환자는 1,088명이였다. 이중임상적으로 TNF-α 길항제의사용이적응되는환자는 109명이였다. TNF-α 길항제사용의적합성판단에관여한류마티스전문의는총 5명으로, 이들의평균류마티스내과임상경력은 12.6 (range 4 19) 년이였다. TNF-α 길항제의사용이고려되는환자들의임상적특징을살펴보면, 성별분포는여자가 87명 (79.8%) 이였고평균연령은 55.9세 (26 81세) 였다 (Table 1). 치료전평균이환기간은 43개월 (1 480개월), 치료기간은 18개월 (3 96개월) 이였다. 류마티스인자는 81.3%, 항CCP 항체는 79.7% 에서양성이였다. 항류마티스약제중 methotrexate는 92% 에서, leflunomide는 50% 에서사용되었고, 스테로이드는 84% 의환자가복용중이였으며, 평균용량은 5±3.2 mg 이였다. 총환자중 67.9% 에서실제로 TNF-α 길항제를사용하였다 (Table 2). TNF-α 길항제사용이고려되는시점에서 DAS28을측정한환자는총 79명이였으며, 평균 DAS28 는 5.2±1.2 (2.1 8) 로 5.1 이상인환자는 50.6% 였다 (Table 3). 평균 ESR은 43.2±29 (range: 1 140) mm/h로 22% 에서정상이었고평균 CRP는 2.5±3.2 (range: ) mg/dl로 61.6% 에서정상이었다. 28개의관절평가에서평균종창관절수 (STC) 는 6개, 평균압통관절수 (TJC) 는 10개였으며, 한국건강보험기준에서명시하는활성관절수 (active joint count) 는평균 5개로보험기준인 20개에매우못미치는것을알수있었다. 또한 12개의대관절중활성관절수도평균 1개였다. TNF-α 길항제의사용이고려되는시점에서 1 Table 1. Characteristics of Korean rheumatoid arthritis patients eligible for TNF-α blocker (N=109) Age (year) Female, N (%) Disease duration (month) (range) Treatment duration (month) (range) RF positive, N (%) ACPA positive, N (%) Baseline ESR (mm/hr) (range) Baseline CRP (mg/dl) (range) 55.9± (79.8) 43.6±91.8 (1 480) 18.3±21.3 (3 96) 78/96 (81.3) 63/79 (79.7) 50.8±32.4 (2 123) 3.2±3.5 ( ) RF: Rheumatoid factor, ACPA:Anti-citrullinated protein antibody, baseline ESR: Erythrocyte sedimentation rate at the start of treatment, baseline CRP: C-reactive protein at the start of treatment. Data are expressed as mean±standard deviation, unless specified otherwise.

3 358 손경민외 Table 2. Medications used by the study subjects of Table 1 (N=109) Current non biologic DMARDs, N (%) Methotrexate Leflunomide Hydroxychloroquine Sulfasalazine Tacrolimus Current biologic DMARDs (%) Etanercept Adalimumab Infliximab Current use of corticosteroid, N (%) Current dose of prednisolone (mg) (mean±sd) 101 (92.6) 55 (50.4) 12 (11) 6 (5.5) 5 (4.5) 32 (29.4) 28 (25.7) 12 (11) 92 (84.4) 5±3.2 Table 3. Profiles of DAS28 in study subjects at the time clinically indicated for eligible for TNF-α blocker (N=79) Current DAS28 (range) SJC in 28 joint (range) TJC in 28 joint (range) Active joint count in 28 joint (range) Active joint count in large joints* (range) ESR (mm/hr) (range) CRP (mg/dl) (range) 5.2±1.28 ( ) 6±5.3 (0 22) 10.6±6.6 (0 28) 5.1±5 (0 22) 1.7±1.6 (0 7) 43.2±29 (1 140) 2.5±3.2 ( ) DAS28: Disease activity score 28, SJC: swollen joint count, TJC: tender joint count, Active joint count: swollen and tender joint within one joint, large joints*: both shoulder, hip, knee, ankle, elbow, wrist, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein. Data are expressed as mean±standard deviation, unless specified otherwise. 년이내에시행한수부및족부단순방사선전, 후방촬영을통하여측정한 van der Heijde s modification of sharp s methods의수치는총 77명에서평가되었으며, 평균미란 (bone erosion score) 수치는 12.11±22.73 (0 125), 평균관절협착지수 (joint space narrowing score) 는 20.64±26.61 (0 115), 평균전체지수 (total score) 는 32.75± 47.1 (0 240) 로다양한범위의수치를보였다 (Table 4). 20% 의환자에서는정상방사선소견을보였다. TNF-α 길항제의사용이고려되는시점에서 TNF-α 길항제의한국건강보험기준을만족하는경우는 5명에서관찰되었다 (4.6%). 한국건강보험기준을만족하지못하는이유를살펴보면, 활성관절수 (active joint count) 의조건을만족하지못하는경우가 81% 로가장높았다 (Table 5). 고찰본연구에서는실제임상에서류마티스전문의가판단하여 TNF-α 길항제의사용이고려되는환자들의임상적특 Table 4. The Profile of Radiographic score measured by van der Heijde s modification score within 1 year at the time clinically indicated for TNF-α blocker Hands erosions (range) (N=77) Hands joint space narrowing (range) (N=77) Hands total score(range) (N=77) Feet erosions (range) (N=56) Feet joint space narrowing (range) (N=56) Feet total score (range) (N=56) Hands and feet erosions (range) (N=53) Hands and feet joint space narrowing (range) (N=53) Hands and feet total score (range) (N=53) 8.06±18.73 (0 109) 17.4±23.62 (0 103) 25.46±39.84 (0 212) 4.96±11.03 (0 69) 3.75±7.11 (0 38) 8.71±16.91 (0 87) 12.11±22.73 (0 125) 20.64±26.61 (0 115) 32.75±47.1 (0 240) Data are expressed as mean±standard deviation, unless specified otherwise. Table 5. Reasons for failing the Korean National Health Insurance reimbursement criteria at the time clinically indicated for TNF-α blocker (N=109) Failed criteria Number (%) Acute phase reactant (ESR or CRP)* Active joint count Previous treatment Hx 27/109 (24.8) 64/79 (81) 21/109 (19.3) Acute phase reactant *: ESR 28 mm/hr or CRP 2 mg/dl, Active joint count : more than 20 total active joint counts or total 6 active joint counts with more 4 active joint count in large joints, Previous treatment Hx : inadequate control despite treatment for at least 3 months respectively with 2 more DMARDs 징을살펴보고, 이환자들중실제한국보험기준의만족여부를조사하였다. 환자들의평균 DAS28은 5.1 이상이었고한국건강보험기준중활성관절개수의조건을 81% 에서만족하지못하였다. 또한임상양상은 DAS28을비롯한종창및압통관절수및염증수치 (ESR 또는 CPR) 등에서다양한범위의분포를나타내었다. TNF-α 길항제에대한사용은주로항류마티스약제사용후질병이잘조절되지않는류마티스관절염환자에게사용이고려되며, 높은약제비및약물유해반응, 장기간사용등을고려하여신중한사용이필요하다 (7). 실제적으로국내에서는건강보험기준을만족하지못하는경우사용이거의불가능하다. 각국가에서제시하는 TNF-α 길항제에대한보험기준및사용기준을살펴보면일본에서는일본류마티스학회에서 TNF-α 길항제의사용권고기준을제시하고있으며종창관절수 (SJC), 압통관절수 (TJC) 가각각 6개이상, ESR 28 mm/hr or CRP 2 mg/dl이고, 적

4 Korean RA Patients Indicated for TNF-α Blocker 359 어도 3개월이상항류마티스약제를사용하였지만질병이잘조절되지않는경우로, 임상의의판단에따라사용이필요하다고고려되는경우보험기준을인정하고있다 (8). 미국류마티스학회생물학적제제사용권고기준은 methotrexate 와같은 DMARD 사용후에도높은질병활성도 (high disease activity) 를보이거나, 중증도의질병활성도 (moderate disease activity) 를보이며나쁜예후인자 (poor prognosis) 를가지는경우이다 (9). 영국류마티스학회권고기준은 methotrexate를포함하여 2가지이상의항류마티스약제를 3개월이상사용하였으며 1달간격으로시행한질병활성도가연속으로 DAS 되는경우이다 (10). 많은나라들에서 TNF-α 길항제에대한보험기준을정하여이를만족하는경우에보험을인정하고있다 (11). 이때사용되는보험기준은나라마다다르지만, 주로종창및압통관절개수, 염증수치, DAS28을사용하고있다. 현재국내에서는조조강직기간, 활성관절수, 염증수치, 과거치료력등이 4가지조건을만족하는경우보험적용이가능하다. 류마티스전문의의판단에따른 TNF-α 길항제의사용적절성과보험기준을비교한논문들을살펴보면, 2008년프랑스에서시행된영국및프랑스류마티스학회의 TNF-α 길항제의권고기준과임상에서류마티스전문의들의판단에따른 TNF-α 길항제의적절성을비교한연구에따르면전체환자 1,132명중 10% 환자에게서류마티스전문의들은 TNF-α 길항제의사용이필요하다고판단하였고, 전체환자중 7% 가프랑스류마티스학회기준을, 0.9% 의환자가영국류마티스학회기준을만족하였다 (12). 류마티스전문의가 TNF-α 길항제의사용이필요하다고판단하는요인에대한분석을살펴보면, DAS28>5.1 이상의높은활성도, 단순방사선소견에서의관절손상의진행, 고용량의스테로이드사용등이있었다. 프랑스와영국류마티스학회기준의충촉률에차이가난점은, 영국류마티스학회기준은 DAS28>5.1 이상의높은활성도기준만판단하였지만, 프랑스학회기준은 DAS28>5.1 이상의높은활성도이외에도중등도의질병활성도를보이는환자에서도활성관절수나염증수치가높은경우, 방사선학적진행여부, 스테로이드의용량여부등도같이고려한점을들수있다. 이로인하여프랑스류마티스학회의기준와류마티스전문의가판단하는 TNF-α 길항제의적절성이좀더유사한만족도분포를보일수있었다. 2009년벨기에서시행한연구에따르면, 이연구에서도벨기에및독일의 TNF-α 길항제의보험기준및류마티스전문의가판단하는 TNF-α 길항제에대한적절성을비교평가하였다 (13). 벨기에의보험기준은우리나라와유사하게 8개이상의종창및압통관절개수, 과거치료력등이포함되어있으며, 이외에도 X-ray 상골미란소견, Health assessment questionnaire (HAQ) 점수를포함하고있고, 독일의보험기준은 1개이상의항류마티스약제사용 후효과가없었던치료과거력과, DAS28>3.2 이상의조건을가지고있다. 총 492명의 methotrexate 을사용한경험이있는활동성류마티스관절염환자가대상이되었으며, 류마티스전문의는이중 27.4% 의환자에서 TNF-α 길항제의사용을고려하였으며, 6.9% 의환자가벨기에보험기준을, 53.4% 의환자가독일보험기준을만족하였다. 벨기에보험기준에대한류마티스전문의의 TNF-α 길항제에대한적합성판단여부를분석해보면, 양성예측치 (positive predictive value, PPV) 는 22.9%, 음성예측치 (negative predictive value, NPV) 는 99.1% 였다. 류마티스전문의가 TNF-α 길항제가필요하다고판단된환자가벨기에보험기준을만족하지못하는이유는우리연구와같이종창관절개수기준이가장많았다 (65.4%). 우리연구의제한점으로는 4곳의대학병원에서시행하였으므로, 대표성에한계가있고, DAS28을기준으로시행된관절평가에서누락되는관절들이있어서활성관절의수가실제보다적게평가되었을가능성이있고이로인하여한국보험기준을만족시키지못하는환자의비율이실제보다높게나타났을가능성이있다. 그리고건강보험의기준은해당나라의국민소득정도와의료재정등에의하여영향을받으므로소득이나국민의료비에서차이를보이는다른나라의권고기준과비교를하는것은제한점이있다. 하지만실제임상에서진료를시행하고있는류마티스전문의가판단하기에 TNF-α 길항제의사용이고려되는환자중다수에서한국보험기준을만족하지못하는것을볼수있었다. 결론본연구에서 TNF-α 길항제의사용이고려되는환자들의임상양상을살펴보면, 평균 DAS28 은 5.1 이상으로높은질병활성도를보였지만, DAS28 및종창및압통관절개수, 염증수치 (ESR 또는 CRP) 등의분포를살펴보면다양한범위의분포를보이는것을알수있었다. 이러한점은현재와같은한국보험기준을적용하는경우, 전체적으로높은질병활성도를보이지만, 보험기준을만족하지못하여실제적으로 TNF-α 길항제의사용이어려운경우가많은것을볼수있다. 그러므로현재의보험기준보다는좀더현실적인기준의제안이필요할것이다. 이를위해서는관절개수및염증수치등의각각의기준보다는전반적인질병활성도를포함할수있는 DAS28와같은기준을보험기준에반영하는것이실제적으로 TNF-α 길항제의사용이필요한높은질병활성도를갖는환자들을선별하는데도움이될것으로사료된다. References 1. Filipovic I, Walker D, Forster F, Curry AS. Quantifying the economic burden of productivity loss in rheumatoid

5 360 손경민외 arthritis. Rheumatology (Oxford) 2011;50: Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999;130: Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48: Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354: Son KM, Jung DM, Kim YB, Han JS, Seo YI, Jung YO, et al. Comparison Korean national health insurance reimbursement and other guidelines for TNF-alpha blocker in rheumatoid arthritis. J Rheum Dis 2012;19: van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 1999;26: Song JS. Review of tumor necrosis factor inhibitors on rheumatoid arthritis. J Korean Rheum Assoc 2007;14: Koike R, Takeuchi T, Eguchi K, Miyasaka N; Japan College of Rheumatology. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod Rheumatol 2007;17: Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al; American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59: Ledingham J, Deighton C; British Society for Rheumatology Standards, Guidelines and Audit Working Group. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005;44: Pease C, Pope JE, Truong D, Bombardier C, Widdifield J, Thorne JC, et al. Comparison of anti-tnf treatment initiation in rheumatoid arthritis databases demonstrates wide country variability in patient parameters at initiation of anti-tnf therapy. Semin Arthritis Rheum 2011;41: Fautrel B, Flipo RM, Saraux A. Eligibility of rheumatoid arthritis patients for anti-tnf-alpha therapy according to the 2005 recommendations of the French and British Societies for Rheumatology. Rheumatology (Oxford) 2008;47: Geens E, Geusens P, Vanhoof J, Berghs H, Praet J, Esselens G, et al. Belgian rheumatologists' perception on eligibility of RA patients for anti-tnf treatment matches more closely Dutch rather than Belgian reimbursement criteria. Rheumatology (Oxford) 2009;48:

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<B0E6C8F1B4EBB3BBB0FA20C0D3BBF3B0ADC1C E687770> 2012 개원의와함께하는임상강좌 경희대학교의학전문대학원류마티스내과학교실 홍승재 진단의중요성 치료의첫단계 : 정확한진단은아무리강조해도지나치지않음 감별진단의중요성 : 진단이달라짐에따라치료시기와약제의선택, 진행경과, 합병증여부, 예후및삶의질에차이가있다. 류마티스관절염 (Rheumatoid arthritis) : 비교적젊은나이에발병하며, 진단초기부터관절염증에의한골파괴소견이가능함.