Cho SK Bae SC Pharmacologic treatment of rheumatoid arthritis Table 1. Drug category and prescription for rheumatoid arthritis treatment Drug category

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1 PHARMACOTHERAPEUTICS J Korean Med Assoc 2017 February; 60(2): pissn / eissn 류마티스관절염의약물치료 조수경 배상철 한양대학교류마티스병원류마티스내과 Pharmacologic treatment of rheumatoid arthritis Soo-Kyung Cho, MD Sang-Cheol Bae, MD Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects the joints. This chronic inflammatory condition causes joint destruction and functional disability, and reduces the quality of life of patients. Therefore, the aims of RA treatment are to control a patient s symptoms by decreasing the inflammation, to prevent joint damage, and to maintain the patient s quality of life while minimizing the progress of the disease. In recent years, the early initiation of disease-modifying anti-rheumatic drugs (DMARDs) has been emphasized because a window of opportunity is thought to exist in early RA, when the disease is more responsive to treatment. Recently, the treatto-target strategy for RA treatment has also been suggested. This strategy involves setting a goal such as remission or low disease state, implementing strict monitoring, and switching the medication regimen promptly as needed. Currently, several DMARDs are available to manage RA. DMARDs form two major classes: synthetic chemical compounds (sdmards) and biological agents (bdmards), which target specific pro-inflammatory cytokines to prevent inflammation. This review summarizes the effectiveness and safety of the current DMARDs available for RA treatment. Tumor necrosis factor inhibitors, T cell costimulation inhibitor, an anti-b cell agent, and the interleukin 6 receptor-blocking monoclonal antibody are classified as bdmards. Tofacitinib, a new sdmard specifically designed to target janus kinases, is also discussed in this article. Key Words: Arthritis, rheumatoid; Drug therapy; Antirheumatic agents 서론 류마티스관절염은특징적으로전신관절을침범하는대표 적인만성자가면역질환이다. 주로손과발의작은관절에서 시작해서큰관절로진행하는데, 활막의염증을시작으로관 절과뼈를손상시켜변형을유발한다 [1]. 환자는만성적으로 Received: December 3, 2016 Accepted: December 19, 2016 Corresponding author: Sang-Cheol Bae scbae@hanyang.ac.kr Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 나타나는관절의통증과시간이경과함에따라나타나는관절의변형으로인해신체장애와삶의질의저하를경험하게되며, 질병의경과및약제의장기복용으로인해피부, 신장및폐등관절외주요장기에동반질환이발생하기도한다 [2]. 자가면역질환중비교적흔하게나타나는질환으로국내유병률 0.3% 정도로보고되고있으며, 주로여성에서나타나고 50-60대연령의유병률이높게나타난다 [3]. 류마티스관절염의약물치료는염증조절및면역조절을통해통증을완화하고질병의진행을조절하여, 관절의손상을막아신체장애를줄이고삶의질을향상시키는것을목표로하게된다 [2]. 따라서, 항염증작용이있는비스테로이드성소염제와글루코코르티코이드 (glucocorticoids) 의사용이중요 156 대한의사협회지

2 Cho SK Bae SC Pharmacologic treatment of rheumatoid arthritis Table 1. Drug category and prescription for rheumatoid arthritis treatment Drug category Drugs that control inflammation and symptom of the disease NSAIDs Glucocorticoid Drugs that can affect the disease itself Conventional DMARD DMARD monotherapy DMARD combination therapy Double DMARD therapy Triple DMARD therapy Description Non-selective or cox-2 inhibitors NSAIDs Low dose 10 mg/day of prednisone (or equivalent) Traditional/conventional DMARDs including HCQ, LEF, MTX, or SSZ (excludes azathioprine, cyclosporine, minocycline, and gold) a) Most often defined as the use of MTX monotherapy, but may also be SSZ, HCQ, or LEF Double or triple traditional/conventional DMARD therapy MTX+SSZ, MTX+HCQ, SSZ+HCQ, or combinations with LEF MTX+SSZ+HCQ Biologic DMRADs TNFi biologic or non-tnf biologic (excludes anakinra) b) TNFi biologics Non-TNF biologics Tofacitinib Adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab Abatacept, rituximab, or tocilizumab (excludes anakinra) Oral synthetic small molecule Modified from Singh JA et al American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016;68:1-26 [5]. NSAID, non-steroidal anti-inflammatory drug; DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; LEF, leflunomide; MTX, methotrexate; SSZ, sulfasalazine; TNFi, tumor necrosis factor inhibitor. a) Azathioprine, cyclosporine, minocycline, and gold were considered but not included in these guidelines due to their infrequent use in rheumatoid arthritis and/or lack of new data since 2012; b) Anakinra was considered but not included in these 2015 American College of Rheumatology guidelines due to its infrequent use in rheumatoid arthritis and lack of new data since 킨다는근거들이제시됨에따라조기진단과조기의적극적인치료가강조되고, 특히질병의활성도가낮은상태나관해에도달하기위해서 3개월마다환자평가를시행하여치료약제를조절하도록하는 T2T (treat to target) 개념이소개되었다 [4-6]. 본논문에서는비스테로이드성소염제와글루코코르티코이드에대한논의는제외하고, 항류마티스제제들을지금까지널리사용되어왔던고전적항류마티스제제와생물학적제제로분류하여소개하고최근새로이국내승인된소분자억제제를소개하고자한다. 고전적항류마티스제제 Table 2. Treatment with conventional disease-modifying antirheumatic drugs in rheumatoid arthritis treatment Dosage Common side effects Serious toxicities Monitoring Methotrexate Hydroxychloroquine Sulfasalazine Lefluomide mg/wk orally or subcutaneous Folic acid 1 mg/d to reduce toxicities Nausea, diarrhea, stomatitis/mouth ulcers, alopecia, fatigue Hepatotoxicity, myelosuppression, infection, interstitial pneumonitis, pregnancy category X CBC, creatinine, LFTs every 2-3 months mg/day orally ( 6.5 mg/kg) Nausea, diarrhea, headache, rash Irreversible retinal damage, cardiotoxicity, blood dyscrasia Funduscopic and visual field testing every 12 months Initial: 500 mg orally twice daily Maintenance: 1,000-1,500 mg twice daily Nausea, diarrhea, headache Granulocytopenia Hemolytic anemia (with G6PD deficiency) CBC every 2-4 wk for first 3 mo, then every 3 mo mg/day Alopecia, diarrhea Hepatotoxicity, myelosuppression, infection, pregnancy, category X CBC, creatinine, LFTs every 2-3 mo Modified from Kasper D et al. Harrison s principle of internal medicine. 19th ed. New York: McGraw-Hill Education; 2015 [9]. G6PD, glucose-6-phosphate dehydrogenase; CBC, complete blood count; LFT, liver function test. 류마티스관절염의치료의기본이되는항류마티스제제는즉각적인증상의완화보다는질병자체의조절을목적으로하므로작용기간이수주에서수개월이걸릴수있다. 흔히사용되는고전적인항류마티스제제들은메토트렉세이트 (methotrexate), 하이드록시클로로퀸 (hydroxychloroquine), 설파살라진 (sulfasalazine) 등이있으며, 효과가없는경우레플루노마이드 (leflunomide) 나 calcineurin 억제제인타크로리무스 (tacrolimus) 가사용된다 [7-12]. 또한, azathioprine, cyclosporine, minocycline, bucillamine, gold와같은약제 들이사용되기도하나그사용빈도는 하며, 항염증작용과면역조절작용을통한질병의조절을목적으로사용되는항류마티스약제들이기본이된다. 최근에는조기에류마티스관절염을진단하여적절한약물치료를시작함으로써관절의변형을예방하고치료결과를향상시 적다. 항류마티스제제들은단독사용또는병합요법이고려될수있다. Table 1에최근 2015년미국류마티스학회 (American College of Rheumatology) 가이드라인을참고하여, 류마티스관절염의약제를분류하고복합용법에대하 류마티스관절염의약물치료 157

3 J Korean Med Assoc 2017 February; 60(2): 여정리하였다 [5]. Table 2에는주로사용하는항약류마티스제제의용량, 부작용, 주의할점을정리하였다 [9]. 1. 메토트렉세이트메토트렉세이트는 1986년류마티스관절염의치료제로승인된후, 효과가좋고모니터링이용이하며심각한독성이드물어항류마티스제제중에서우선적으로사용된다. 메토트렉세이트는세포내로유입된후항염증과정과항증식작용에관여하는여러효소들에작용한다. 대표적작용기전으로는아데노신을증가시켜림프구, 단핵구, 중성구의표면에있는특정수용체에결합하여염증과정을억제하고혈관을확장시켜혈소판응집을억제하는효과가있다. 또, 피리미딘합성을억제, DNA 합성과세포기능에중요한 transmethylation 반응을억제한다. 메토트렉세이트단일요법은효과적이지만, 메토트렉세이트단일요법만으로는질병의활성도가없는관해상태의유도가어려울수있기때문에질병조절이충분하지않다면다른항류마티스제제를병용투여하는것이필요하다. 초기용량은일반적으로 mg을주 1회경구복용하고최대 mg까지점차증량한다. 대부분의경우복용이용이한경구제제로투여를시작하고위장관증상이나생체이용률을고려하여피하또는근육주사로변환하기도한다. 주된부작용은구강궤양, 오심, 간독성, 골수억제, 간질폐렴이다. 피부증상, 위장관증상, 골수억제등의대부분의부작용은메토트렉세이트용량및엽산결핍과관련이있어서용량감량이나엽산을함께복용하여부작용을줄일수있다. 성을막기위해서는하이드록시클로로퀸은 6.5 mg/kg 이하, 일반적으로하루에최대 400 mg을넘지않게사용한다. 피부발진, 두드러기, 광과민성, 탈모, 탈색이일어날수있으나, 투약중지후에는대부분신속히소실된다. 망막독성은가장심각한부작용으로적절한용량사용과모니터링이필요하다. 망막병증의위험인자로는고용량 (>5 mg/kg), 긴사용기간 (>5 년 ), 총누적투여량 >1,000 g, 신기능장애, 고령이있다 [13,14]. 진행되면비가역적인시력손실이오고약물을중단후에도지속될수있기때문에초기에진단하는것이필요하다. 3. 설파살라진설파살라진은 1938년류마티스관절염치료제로소개된합성물로주로메토트렉세이트와하이드록시클로로퀸와의병합요법으로사용된다. 설파살라진은 5-아미노살리실산 (aminosalicylic acid) 과설파피리딘의합성물로, 과거에는항균작용으로장관내세균총을변화시켜염증성관절염을일으키는면역반응을억제할것이라고생각되었으나최근항염증작용과면역조절작용이더주된기전으로알려져있다. 메토트렉세이트처럼아데노신분비를촉진하고, 중성구의화학주성과이동, 단백분해효소의생산과분비를감소시키고류마티스관절염의활막염에관여하는내피세포와섬유모세포의분화와혈관신생을억제한다. 500 mg 하루 2회복용으로시작하여점차증량하여 1,500-3,000 mg을매일 2회로나누어복용한다. 소화기계부작용, 두통, 어지러움, 발진이주로나타난다. 2. 하이드록시클로로퀸경증이거나중증의환자에서다른항류마티스제제와병합요법으로고려한다. 약염기성으로세포막을통과하여세포질소포내에축적되고 ph를높인다. 소포내 ph가높아지면리소좀막이안정되고항원처리와표현의감소, 세포매개세포독성이억제되어대식세포와단핵구의기능이억제된다. 또한 interleukin 1, interleukin 6, tumour necrosis factor 같은염증성사이토카인생성을억제하고자가반응림프구를제거함으로써자가면역을감소시킨다. 경구제제로안구독 4. 레플루노마이드레플루노마이드는 1997년류마티스관절염의치료제로승인되었고단일요법및메토트렉세이트와의병합요법모두효과적이다. 레플루노마이드는전구약물로서체내에서흡수되면빠르게활성물질인 A 으로변환된다. 류마티스관절염에서의정확한기전은알려져있지않지만, 주된작용으로피리미딘합성경로에필수적인디히드로오로트산탈수소효소 (dihydroorotate dehydrogenase) 를억제하고고농도에서는티로신키나아제를억제하여세포신호전달을방해 158 대한의사협회지

4 Cho SK Bae SC Pharmacologic treatment of rheumatoid arthritis Table 3. Treatment with biologic disease-modifying antirheumatic drugs in RA Group Target Drug Dosage Injection Anticytokines or cytokine receptor antagonists Inhibitors of cellular activation TNF inhibitors Etanercept 25 mg (or 50 mg) IL-6 receptor blockade IL-1 blockade T-cell modulation (CTLA-4-Ig) B-cell modulation (anti-cd20 antibody) Twice/wk (or once/wk), SC Adalimumab 40 mg Once/2 wk, SC Infliximab 3 mg/kg (RA) 0, 2, 6 wk, then every 8 wk, IV Golimumab 50 mg Once/4 wk, SC Certolizumab Tocilizumab Anakinra (not approved in Korea) Abatacept 200 mg (or 400 mg) 8 mg/kg (SC, 162 mg) Once/2 wk (or once/4 wk), SC Once/4 wk, SC (once/2 wk, SC) mg (or 750 mg) (SC, 125 mg) 0, 2, 4 wk, then every 4wk, IV (once/wk, SC) Rituximab 1,000 mg Two doses is administered on 0 and 2 wk, then every 6 mo, IV TNF, tumor necrosis factor; SC, subcutaneous; RA, rheumatoid arthritis; IV, intravenous; IL, interleukin; CTLA 4, cytotoxic T-lymphocyte-associated antigen 4. 제하는약제와세포의활성화를억제하는약제로나누어표적물질과사용법을 Table 3에정리하였다. 1. 항시토카인치료 1) 항종양괴사인자제제 (Etanercept, infliximab, adalimumab, golimumab, certolizumab) 종양괴사인자는우리몸을보호하는중요한역할을하지만, 비정상적으로조절될때염증반응을유발하여자가면역질환이나타나게된다. 항종양괴사인자제제는생물학적제제중가장먼저개발되어사용되고있는약제로종 양괴사인자기능을억제하여염증유발 할것으로생각된다. T 세포활성화과정에는새로운피리미딘과퓨린생합성이필요한데, 이과정을방해하여휴지기의림프구보다는주로활성화된 T 림프구를감소시켜면역조절작용을한다. 일반적으로매일 20 mg 복용을유지하고, 부작용이있거나질병이잘조절될경우 10 mg으로감량한다. 주된부작용은간기능악화, 설사, 발진, 탈모이다. 주성분인 A 은반감기가길기때문에투약을중단한후에도이상반응이나타나거나지속될수있고, 심각한부작용이발생하는경우, 콜레스티라민을투여하여제거하여야한다. 시토카인생성을감소시키고, 관절내림프구의이동을억제하며관절안의혈관생성을감소시켜효과가나타난다. 항종양괴사인자제제는주로메토트렉세이트와병행하여사용한다. 항종양괴사인자제제는약제에따라작용기전및약물용량및주입방법이조금씩다르다. Infliximab은정맥투여약제로주사시반응이나타날수있는데, 두통, 오심, 두드러기, 가려움, 열, 호흡곤란이생길수있으며아세트아미노펜, 항히스타민, 단기작용스테로이드등을사용하여치료한다. Etanercept나 adalimumab은피하주사 로주사부위의통증, 발적, 가려움, 두드러기등이발생할 생물학적제제 수있으나, 발생빈도가적고약물을중단할만큼심한경우 는드물다. 약제에대한항체가발생하여면역복합체를형 성하거나과민증을보일수있으며, 메토트렉세이트와병 생물학적제제는유전자재조합기술을이용하여만들어진항체나그와유사한물질로서, 류마티스관절염의발병에관여할것으로생각되는물질이나세포의기능을차단하는역할을함으로써치료에이용된다. 기존항류마티스약제에효과가부족한환자들의증상및예후호전을위하여표적물질을직접차단하는생물학적제제들의연구및사용이증가되었다 [15,16]. 현재사용되고있는주요생물학적제제들은관련물질과세포에따라서 cytokine의기능을억 용사용하는경우 infliximab과 adalimumab에서항체생성률을감소시킬수있다. Certolizumab은국내허가되어있으나사용되지는않고있다. 최근에는항종양괴사인자제제들에대한바이오시밀러 (biosimilar) 제제들의개발이국내제약사들을중심으로활발히진행되어현재는진료현장에서함께사용중이며, 바이오시밀서제제들은기존의오리지널제제와비교하여서유사한효과를보이는것으로보고되고있다 [17]. 종양괴사인자는육아종발생에중 류마티스관절염의약물치료 159

5 J Korean Med Assoc 2017 February; 60(2): 요한역할을하기때문에항종양괴사인자제제를사용시마이코박테리아감염에적절한숙주방어를하지못해결핵발생의위험이높아진다 [18]. 따라서, 항종양괴사인자제제를사용하기전잠복결핵검사를시행하여치료하는것이권고된다. 국내에서는잠복결핵의선별검사로투베르쿨린피부반응검사와인터페론감마반응검사를실시하여한가지라도양성인경우예방치료를권장하고있다 [19]. 림프종발생비율이약간증가하는연구결과가있으나, 고형종양의발생은증가시키지않는다. 심부전의악화, 치료초기에범혈구감소증또는재생불량빈혈의발생, 간독성등의발생이보고되어적절한모니터링과주의가필요하다. 2) Interleukin 6를표적으로하는항 interleukin 6 수용체항체 (tocilizumab) Interleukin 6는류마티스관절염의발병기전에중추적인역할을하는시토카인중하나로, tocilizumab은인간유도단클론항체로 Interleukin 6의수용성수용체나세포막수용체와결합하여염증반응을억제한다. Tocilizumab은단독요법또는메토트렉세이트와병용사용이모두가능하다. Tocilizumab의흔한부작용은간수치상승, 백혈구와혈소판수치감소, 콜레스테롤수치증가가나타날수있다. 심각한감염의비율은다른생물학적제제와차이가없었으며, 장천공, 연부조직감염이종종보고되어이에대한주의가필요하다 [20]. 2. 세포의활성화를억제하는약제 1) T 세포를표적으로하는 abatacept T 세포가활성화되기위해서는 T 세포수용체에주조직적합복합체가결합하여발생하는항원-특이신호뿐아니라 T 세포표면의 CD28과항원제시세포의 CD80/CD86 의결합에의한항원-비특이이차신호가필요하다. 활성화된 T 세포는표면에 cytotoxic lymphocyte-associated antigen-4를발현시키고, CD80/CD86과결합하여 T 세포의활성화를억제하게된다. 이러한면역메카니즘을표적으로만들어진약제가 abatacept이다. Abatacept는 cytotoxic lymphocyte-associated antigen-4의세포외 domain을면역글로불린 G1의 Fc 부위에결합시킨수용 성단백질로, CD80/86과결합하여 T 세포의활성을억제한다. 메토트렉세이트치료에불충분한반응을보이는경우사용하며, 단독및항류마티스제제와의병용치료모두가능하다. 흔한합병증은두통, 상부호흡기감염, 인후두염및오심이다. 항체반응과관련된부작용은보고되지않았으며, 결핵의발생또는잠복결핵의활성화가동물실험에서발견되지는않았지만, 실제임상에서는항종양괴사인자제제와동일하게치료전잠복결핵에대한검사및예방치료를시행한다. 2) B 세포를표적으로하는 rituximab Rituximab은성숙한 B 세포의표면에만선택적으로발현하는 CD20 에직접적으로반응하여 B 세포를제거하는단클론항체이다. Rituximab이 B 세포를제거하는기전은잘알려져있지않지만, 항체의존세포독성및보체의존세포독성을통해세포자멸사를유발하고세포를파괴시킨다. 이를통해, B 세포의항원제시세포기능을막고, 관련된시토카인의생성을막아 T 세포의활성을억제시키는것으로알려져있다. Rituximab은항종양괴사인자제제의치료에반응이없는환자들을대상으로단독및메토트렉세이트와병합치료를시행한다. 부작용은주사시반응이가장흔하며, B 세포가파괴되면서다량의시토카인이방출되면서나타나는것으로알려져있다. 첫번째치료시주입반응이나타나는빈도가가장높으며, 이후에는점차감소하는것으로알려져있으며, rituximab 치료전스테로이드를정맥투여하면발생을예방할수있다. 드물지만다초점뇌백질증후군이발생할수있으며, 심부전환자, B형간염, HIV 감염, 백혈구감소증, 저감마글로불린혈증환자에서는주의해야한다. 소분자억제제 소분자억제제라는새로운시도의약제는류마티스관절염의발생기전에기반하여표적분자를정한다는점에서생물학적제제와유사하지만, 항체의형태가아닌화합물의형태로제조된다는차이점이있다. 따라서표적합성항 160 대한의사협회지

6 Cho SK Bae SC Pharmacologic treatment of rheumatoid arthritis 류마티스제제로명칭되기도한다. Small molecules 은 1 kda 미만의화합물분자로세포내에서일어나는다양한염증반응을차단하고자하며, 반감기가짧고, 생물학적제제들과달리경구복용이가능하며제조비용을낮추는것이가능하다는큰장점이있다. 대표적인소분자억제제로 Janus activated kinase (JAK) 억제제인 tofacitinib이많은임상시험이진행되어최근임상에서사용이가능해졌으며, 국내에서도승인이되었다. JAK 분자는염증성사이토카인의세포내수용체에위치하여, 염증성사이토카인의시그날을세포내로전달하는역할을하며, tofacitinib 은 JAK 분자중에서도 JAK-1과 JAK-3을차단하는것으로알려져있다 [21]. 대표적인임상시험결과, tofacitinib은항류마티스제및생물학적제제에효과가없는환자를대상으로투여하였을때에모두위약군에비하여효과적인것으로나타났으며, 한연구결과에서는 adalimumab과유사한효과를보이기도하였다 [22]. 또한, methotrexate를동반사용하였을때와하지않았을때에모두효과를보였다. 주로보고되었던안전성관련문제는감염이었는데, 상기도감염이주로보고되었고, 결핵발생, 최근에는대상포진의발생과의관련성보고가있었다. 또한, 콜레스테롤의상승, 간수치상승, 혈구수치감소등의관련성이제시되었다 [23]. 국내환자들을대상으로도진행된연구에서도 tofacitinib은류마티스관절염의방사선학적진행에효과를보였다 [24]. 의세포, 분자적단계에서의이해가조금씩가능해지게되었고이는새로운치료약제의개발로지속적으로이어지고있어환자들과임상의사들과환자들에게큰희망을주고있다. 또한, 다양한다양한기초연구및임상연구들덕분에현재류마티스관절염의치료목표와치료방법, 결과는과거와는비교할수없을만큼향상되었다. 그러나, 약제들의장기간사용과관련한효과와안전성문제뿐아니라, 새로운약제들의고비용과관련된개인적, 사회적측면에서의경제적문제가여전히남아있다. 특히, 항류마티스제제로치료를시작하고난후, 질병의활성도조절이불충분한경우생물학적제제로의변경은항류마티스제제의복합요법으로변경하는경우보다질병관해도달률이조금높은경향을보였으나다양한성과지표에대한검토와경제적측면이함께고려될필요가있다 [25]. 또한, 약제선택의폭이넓어짐에따라서어떤환자들에게어떤약제를선택하는것이가장적절할것인가에대한고민등은새롭게대두된중요한문제이므로이러한부분을해결하기위한약물역학연구가더욱활발히이루어질필요가있다. 다양한임상연구들을통하여환자의증상조절뿐아니라, 신체장애발생을예방혹은개선하고삶의질을향상시키기위해보다적절한치료전략을수립하고자하는노력들이더해지면서, 류마티스관절염에대한인식은과거와는다르게빠르게변하고있으며, 더나아가머지않은미래에진정한의미에서의완치가능성을기대해볼수있을것이다. 국내에서는 2015 년메토트렉세이트에효과가없는중등 도이상의활성도를보이는류마티스관절염환자에서단독 용법또는항류마티스제제병용요법으로승인이되었다. 현 찾아보기말 : 류마티스관절염 ; 약물치료 ; 항류마티스제제 재국내급여기준은, 적어도 1 개이상의생물학적제제에반 응하지않거나내약성이없는중등도이상의활성도를보이 는류마티스관절염환자의경우에한정된다. ORCID Soo-Kyung Cho, Sang-Cheol Bae, 결론 류마티스관절염이발생하는직접적인원인은아직명확히 밝혀지지않았지만, 최근눈부신과학의발전에힘입어질병 REFERENCES 1. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010;376: 류마티스관절염의약물치료 161

7 J Korean Med Assoc 2017 February; 60(2): Tiippana-Kinnunen T, Kautiainen H, Paimela L, Leirisalo- Repo M. Co-morbidities in Finnish patients with rheumatoid arthritis: 15-year follow-up. Scand J Rheumatol 2013;42: Sung YK, Cho SK, Choi CB, Bae SC. Prevalence and incidence of rheumatoid arthritis in South Korea. Rheumatol Int 2013; 33: Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, Emery P, Gaujoux-Viala C, Gossec L, Nam J, Ramiro S, Winthrop K, de Wit M, Aletaha D, Betteridge N, Bijlsma JW, Boers M, Buttgereit F, Combe B, Cutolo M, Damjanov N, Hazes JM, Kouloumas M, Kvien TK, Mariette X, Pavelka K, van Riel PL, Rubbert-Roth A, Scholte-Voshaar M, Scott DL, Sokka-Isler T, Wong JB, van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73: Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, Curtis JR, Furst DE, Parks D, Kavanaugh A, O'Dell J, King C, Leong A, Matteson EL, Schousboe JT, Drevlow B, Ginsberg S, Grober J, St Clair EW, Tindall E, Miller AS, McAlindon T American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016;68: Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, Kvien TK, Navarro-Compan MV, Oliver S, Schoels M, Scholte-Voshaar M, Stamm T, Stoffer M, Takeuchi T, Aletaha D, Andreu JL, Aringer M, Bergman M, Betteridge N, Bijlsma H, Burkhardt H, Cardiel M, Combe B, Durez P, Fonseca JE, Gibofsky A, Gomez-Reino JJ, Graninger W, Hannonen P, Haraoui B, Kouloumas M, Landewe R, Martin- Mola E, Nash P, Ostergaard M, Ostor A, Richards P, Sokka- Isler T, Thorne C, Tzioufas AG, van Vollenhoven R, de Wit M, van der Heijde D. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 2016;75: Firestein GS, Kelley WN. Kelleyʼs textbook of rheumatology. 9th ed. Philadelphia: Elsevier; Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH. Rheumatology. 5th ed. Philadelphia: Mosby; Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J. Harrison s principle of internal medicine. 19th ed. New York: McGraw-Hill Education; Cecil RL, Goldman L, Schafer AI. Goldman s cecil medicine. 24th ed. Philadelphia: Elsevier; Klippel JH. Primer on the rheumatic diseases. 13th ed. New York: Springer; Lee WS, Lee SI, Lee MS, Kim SI, Lee SS, Yoo WH. Efficacy and safety of low-dose tacrolimus for active rheumatoid arthritis with an inadequate response to methotrexate. Korean J Intern Med 2016;31: Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118: Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF; American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology 2016;123: Hong MJ, Yoo WH. Biologic agents in rheumatic diseases. Korean J Med 2012;82: Kim J, Song YW. Medical treatment of rheumatoid arthritis (II): current biologic agents and newly developing drugs. J Korean Med Assoc 2010;53: Sung YK, Cho SK, Kim D, Won S, Choi CB, Bang SY, Hong SJ, Kim HA, Koh EM, Lee HS, Suh CH, Yoo DH, Bae SC. Characteristics and outcomes of rheumatoid arthritis Patients who started biosimilar infliximab. Rheumatol Int. In press 18. Seong SS, Choi CB, Woo JH, Bae KW, Joung CL, Uhm WS, Kim TH, Jun JB, Yoo DH, Lee JT, Bae SC. Incidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers. J Rheumatol 2007;34: Joint Committee for the Revision of Korean Guidelines for Tuberculosis, Korea Centers for Disease Control and Prevention. Korean guidelines for tuberculosis. 1st ed. Cheongju: Joint Committee for the Revision of Korean Guidelines for Tuberculosis, Korea Centers for Disease Control and Prevention; Sakai R, Cho SK, Nanki T, Watanabe K, Yamazaki H, Tanaka M, Koike R, Tanaka Y, Saito K, Hirata S, Amano K, Nagasawa H, Sumida T, Hayashi T, Sugihara T, Dobashi H, Yasuda S, Sawada T, Ezawa K, Ueda A, Fujii T, Migita K, Miyasaka N, Harigai M; REAL Study Group. Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry. Arthritis Res Ther 2015; 17: Tanaka Y. Current concepts in the management of rheumatoid arthritis. Korean J Intern Med 2016;31: Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, Connell CA, Gruben D, Krishnaswami S, Wallenstein G, Wilkinson BE, Zwillich SH. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or 162 대한의사협회지

8 Cho SK Bae SC Pharmacologic treatment of rheumatoid arthritis adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012;64: Lee EB. Small molecule inhibitors in rheumatoid arthritis. J Rheum Dis 2012;19: Kim JW, Choi IA, Lee EY, Song YW, Lee EB. Tofacitinib prevents radiographic progression in rheumatoid arthritis. J Korean Med Sci 2013;28: Sung YK, Cho SK, Kim D, Choi CB, Won S, Bang SY, Cha HS, Choe JY, Chung WT, Hong SJ, Jun JB, Kim HA, Kim J, Kim SK, Kim TH, Lee HS, Lee J, Lee J, Lee SS, Lee SW, Lee YA, Nah SS, Suh CH, Yoo DH, Yoon BY, Bae SC; BIOPSY and KORONA investigators. Comparative effectiveness of treatment options after conventional DMARDs failure in rheumatoid arthritis. Rheumatol Int 2017 Jan 28 [Epub]. org/ /s Peer Reviewers Commentary 본논문에서는현재류마티스관절염치료에사용되고있는항류마티스약제의기전과표준사용법을소개하고있다. 류마티스관절염은최근과학의발전으로질병의세포, 분자단계의병리기전에대한이해가높아졌으며, 병리기전을근거로한새로운치료약제가개발되어현재치료에빠른속도로적용되고있다. 국내에서사용가능한고전적항류마티스제제, 생물학적제제및소분자억제제의효과와부작용에대해국내문헌을포함한최신논문을근거로하여잘정리하고있어류마티스관절염치료에도움을줄것으로판단된다. 특히생물학적제제의효과뿐만아니라용량및부작용도자세히기술되어있어약물을선택할때기준점이될수있는논문이다. [ 정리 : 편집위원회 ] 류마티스관절염의약물치료 163

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon