68 Hanyang Medical Reviews Vol. 32, No. 2, 2012 http://dx.doi.org/10.7599/hmr.2012.32.2.68 류마티스관절염의생물학적제제 박성훈, 김성규, 최정윤대구가톨릭대학교의과대학류마티스내과 Sung-Hoon Park, M.D., Ph.D., Seong-kyu Kim, M.D., Ph.D., Jung-Yoon Choe, M.D., Ph.D. Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea 책임저자주소 : 최정윤, 708-718, 대구광역시남구두류공원로 17 길 33 대구가톨릭대학교의과대학마리아관 Tel: 053-650-4289, Fax: 053-629-8248 E-mail: jychoe@cu.ac.kr 투고일 : 2012 년 2 월 20 일, 심사일 : 2012 년 3 월 13 일, 게재확정일 : 2012 년 4 월 20 일 Abstract Decades of accumulated knowledge and improved comprehension of various perspectives on rheumatoid arthritis (RA) pathophysiology has led to the development of new biologic agents that inhibit a specific component of the RA inflammatory process. Especially during the last two decades, several epochal agents which target tumor necrosis factor-α, interleukin-1, interleukin-6, CD20-expressing B cell, and cytotoxic T lymphocyte antigen-4 were used in the management of RA and other autoimmune diseases with highly comparable efficacy and safety. Moreover, dozens of innovative agents queue up for clinical trials day by day. Herein, we review the current scenario of RA management in terms of pathogenesis and targeted molecular pathways, and some important controversies in this field as well. Based on the complications that these kinds of diseases pose, it is highly reasonable to hope that further improved therapies and more tailored drugs for RA will be introduced in the near future. Key Words: Arthritis, Rheumatoid; Biologic Agents; Therapeutics 서론 1980년대까지류마티스관절염의치료는소위 피라미드접근방식 이라고하는, 물리치료와같은비약물적치료에이어비스테로이드성항염제와항류마티스약물을하나씩추가하는방식의, 천천히증량되는치료방식을고수하였다 [1]. 이후조기에위험군환자에대해항류마티스약물을병합투여함으로써관절의손상과기능장애를줄일수있다는발상의전환이이루어졌고 [2], 이와더불어면역학과분자생물학, 유전자역학등류마티스관절염의병인에대한연구가이루어지면서이런병인에관여하는표적물질을직접차단하는생물학적제제에대한연구와임상시험이폭발적으로증가하게되었다. 1990년대후반부터환자들에게투여되기시작한종양괴사인자알파 (tumor necrosis factor-α) 차단제를위시하여 B 세포차단제, 이차신호차단제, IL-1/IL-6 차단제등다양한병인관련물질을선택적으로차단하는약제들이개발되어류마티스관절염의치료성적과장기예후를개선시키는데크게도움을주었으며, 발달된유전자재조합기술과분자병리학적연구에힘입어다수의표적후보물질들이상용화가능성을시험받고있다 (Fig. 1) [3, 4]. 저자들은이글에서현재사용되거나임상시험중인생물학적제제의종류와효과에대해기술하고향후류마티스관절염에대한새로운표적치료의발전가능성에대해알아본다.
69 Fig. 1. Targets of biologic agent in rheumatoid arthritis. OC, osteoclast; DC, dendritic cell; FLS, fibroblast-likesynoviocyte; MΦ, macrophage; RANKL, Receptor activator of nuclear factor kappa B ligand; TGF-β, Transforming growth factor beta; TNF-α, Tumor necrosis factor alpha; Syk, Spleen tyrosine kinase; Tyk, Tyrosine kinase; CC, β -chemokine; CXC, α-chemokine; GM-CSF, Granulocyte macrophage-colony stimula ting factor; Th, T helper IL, Interleukin; CD, Cluster of differentiation. 본론 : 생물학적제제의종류와사용현황 1) Infliximab 1. 종양괴사인자차단제류마티스활막염의병리기전에여러시토카인 (cytokine) 이관여하는것이밝혀졌고, 특히그중에서도단핵구및대식세포에서분비하는종양괴사인자알파가시토카인과케모카인의발현, 혈관내피세포부착분자의발현, 활막세포의분화, 신생혈관생성의촉진, 조절 T세포 (regulatory T cell, Treg) 의억제, 통증의유발등에중요한역할을하는것이밝혀져서생물학적제제의치료표적으로가장먼저개발되었고가장많이사용되고있다 [5-7]. 현재까지 5종류의종양괴사인자차단제가시판되었거나임상시험이진행중이다. 각각의종양괴사인자차단제는제조방법이나투여방법, 작용기전및그효과와부작용에있어서약간의차이를보인다 [8]. 최근에는한가지종양괴사인자차단제에부작용이나타나거나효과가불충분한경우다른계열의약제로교차투여하는것이관해에도달할수있는방법의하나로알려져있다. Infliximab은가장먼저개발된종양괴사인자차단제로서종양괴사인자알파에대한이종단백질과인간단백질이결합한키메라단클론항체 (chimeric monoclonalantibody) 이다. 종양괴사인자와결합하는 25% 정도의가변영역 (VK, VH damain) 은쥐에서유래하고 75% 정도의 Fc영역은인간유래단백질이며 [9] 수용성종양괴사인자와세포막에결합된종양괴사인자모두에결합한다. Infliximab은미국에서 1998년크론병에대해승인을받았으며 [10] 류마티스관절염에대해서는 1999년메토트렉세이트와같이사용하는것으로승인을받았다. 초기 0주, 2주, 6주에 3 mg/kg 으로정맥주사하며, 투여효과와부작용을검토한뒤 8주마다유지요법으로투여할수있다. 대규모의전향적무작위배정연구에서메토트렉세이트와병용투여시대조군에비해유의한 ACR20 (american college of rheumatology 20, 다른임상적증상과검사실소견의호전과함께압통관절과부종관절의수가동시에최소한 20% 이상감소하는환자의수 ) 반응과임상증상및염증반응수치의호전을보였다 [11, 12]. 국내에서도 2000년대초반이후부터활동성류마
70 Hanyang Medical Reviews Vol. 32, No. 2, 2012 티스관절염과강직성척추염환자에게사용되어좋은효과를나타내고있다. 2) Etanercept Etanercept는종양괴사인자에대한수용성수용체로써 2 개의 p75 수용체융합단백질이면역글로불린 G1의 Fc영역과결합된형태를취하며혈중종양괴사인자와결합하여실제수용체와결합하는것을방해한다 [13]. Etanercept 는 1998 년미국에서류마티스관절염치료제로승인받았으며우리나라에서는 2004년부터사용되고있다. 활동성류마티스관절염환자에서 25 mg, 주 2회혹은 50 mg, 주 1회피하주사를원칙으로하며활동성류마티스관절염환자를대상으로한대규모무작위배정대조군연구에서 Etanercept 와메토트렉세이트병합요법이각각의단독요법보다질병활성도조절과기능장애호전, 방사선학적골파괴감소및삶의질향상에도움이되는것으로확인되었다 [14-16]. 3) Adalimumab Adalimumab은종양괴사인자에대한최초로 100% 인간화된단클론항체이며인간면역글로불린 G1과구조적으로유사하다. 2주마다 40 mg을피하주사하며, 북미지역에서행해진대규모임상시험에서메토트렉세이트와함께투여시류마티스관절염질병활성도를빠르게호전시키는것으로보고되었고 [17], 발병 3년이내의조기류마티스관절염환자에서임상증상의호전과방사선학적골파괴를효과적으로막을수있는것으로나타났다 [18]. 2002년말에미국 FDA 승인을받았으며우리나라에서는 2007년부터사용되고있다. 4) Certolizumab 새로운종양괴사인자차단제인 Certolizumab은인간화된 Fab 분절과 40 kd polyethylene glycol (PEG) 을결합시켜약제반감기를늘여염증조직에더오래분포되도록한단클론항체이다. 크론병과류마티스관절염환자에서임상시험이행해졌으며, 활동성류마티스관절염환자를대상으로한대규모연구에서메토트렉세이트와함께 Certolizumab 200 mg을 2주에한번피하주사시위약에비해질병활성도의조절, 관절파괴의억제, 기능의호전등에의미있게효과가있는것으로나타났다 [19]. 우리나라류마티스관절염환자를대상으로 2012년현재 3상임상시험이행해지고있다. 5) Golimumbab 인간화단클론항체인 Golimumab 은다수의대규모임상시험을통해메토트렉세이트불응성류마티스관절염환자의질병활성도조절과 [20] 한가지이상의다른종양괴사인자차단제에효과가없었던환자에서도효과가있음을보여주었다 [21]. 국내에서도 3상임상시험이진행되었으며 50 mg을한달에한번피하주사한다. 2. Interleukin-1 (IL-1) 억제제 : Anakinra ( 항IL-1Ra, 수용체길항제 ) 여러연구들을통해활막염의악화와관절파괴의진행에있어 IL-1이중요한역할을하는것이밝혀지게되어이시토카인을표적으로하는연구가진행되었다. IL-1 수용체길항제는류마티스활막에자연적으로존재하는급성기반응, 항염증단백질로써, IL-1이 type 1 수용체와결합하는것을막는다. 항 IL-1 수용체길항제는유전자재조합으로만들어진단클론항체로여러임상시험에서메토트렉세이트와병용투여시 ACR20이유의하게차이나는것으로보고되었으나 [22], 종양괴사인자차단제에비해효과가적은것으로생각되고피하주사용량에따라감염의위험성이증가하여종양괴사인자차단제가실패한경우고려해볼수있는것으로권고되고있으며 [23], 성인형스틸씨병이나 cryopyrin 연관질환에서좋은효과를보이고있다. 3. Interleukin-6 (IL-6) 억제제 IL-6는류마티스관절염환자의급성기에혈액과관절내에많이존재하는염증성시토카인의하나로알려져있다. 수용성수용체나세포막수용체의 gp130과반응하여세포내로신호전달을하며 T세포및 B세포의활성화, 파골세포의활성화와분화, 연골세포의손상등여러병리적현상에
71 관여한다 [7, 24]. Tocilizumab은인간화된항 IL-6 수용체단클론항체로써세포막결합형혹은유리형 IL-6 수용체와결합하여 IL-6의염증발현작용을억제한다. 메토트렉세이트에불충분한반응을보이는활동성류마티스관절염환자에게투여시용량에비례하여질병활성도와염증반응수치에효과적인작용을나타내었다 [25]. 미국, 유럽및일본에서사용중에있으나아직국내에서는시판되지않았다. 4 mg/kg 용량을 4주간격으로정맥주사한다. 최근새로운세대의인간화 IL-6 수용체단클론항체인 REGN88/SAR153191이피하주사의형태로 1상임상시험중에있으며 [26], 또다른표적치료의하나로 IL-6를직접적으로차단하는항 IL-6 단클론항체인 ALD518이 2상시험중에있어향후 IL-6를표적으로하는치료제들이더많이상용화될수있는가능성을보여주고있다 [27]. 4. Interleukin-17 (IL-17) 억제제고전적인 CD4+ T세포로부터 Th1, Th2 계열세포로의분화이외에 IL-17을분비하는 Th17 세포의존재가알려졌으며, 이시토카인이염증반응과자가면역의조절에중요한작용을하는것으로밝혀졌다. 항 IL-17A 단클론항체인 Secukinumab (AIN457) 이활동성류마티스관절염환자에사용되어 2상임상시험중에있다 [28, 29]. 5. T세포이차신호억제 (costimulatory signal blockade) 항원제시세포에의한 T세포의활성화에는항원제시세포의주조직적합복합체와 T세포수용체와결합이외에T세포표면의 CD28/CTLA4 (cytotoxic T lymphocyte associated antigen 4) 와항원제시세포의 CD80/86 배위자의결합과같은이차신호가중요하다 [30]. Abatacept는 CTLA4 면역글로불린으로 CTLA4의세포외 domain을면역글로불린 G1의 Fc 부위에결합시킨수용성단백질이다. 높은친화성으로 CD80/86과경쟁적으로결합하여 T세포의활성화를억제한다. 항류마티스약물을투여받은적이없는조기류마티스관절염환자를대상으로한연구에서메토트렉세이트와Abatacept 병용투여군에서 1 년째 ACR50, ACR70 반응과기능장애의개선이유의하게 높았고, 2년연장연구에서도비슷한결과를보였다 [31, 32]. 메토트렉세이트에불충분한반응을보이는활동성류마티스관절염환자를대상으로한연구에서 1년후유의하게높은 ACR20 반응과관절손상의진행을막는것이확인되었다 [33]. 마찬가지로종양괴사인자차단제에불충분한반응을보이는환자를대상으로한연구에서도대조군에비해질병활성도감소와기능회복에유의하게좋은결과를보였다 [34]. 미국에서는 2005년 FDA 승인을받았고우리나라에서는 2011년시판되어환자들에게투여되고있다. 2012 년현재우리나라의조기류마티스관절염환자를대상으로피하주사의효과와안정성에대한 3상임상시험이수행되고있다. 6. B세포제거과거에류마티스관절염이주로 T세포에의한면역질환으로인식되다가종양괴사인자, IL-1 등의시토카인이병인에관여하며이런물질들을차단하는것이좋은효과를보이는것을발견하는패러다임의전환이이루어졌다. 이후염증반응의진행에있어 B세포의역할이밝혀지게되었고, 이런 B세포를차단하는것이류마티스인자나항 CCP 항체를생성하는형질세포로의분화를막고, B세포의항원제시세포로서의기능을막으며, T세포활성화를위한이차신호발현을막고, lymphotoxin이나 IL-4, IL-6, IL-10 등의시토카인생성을조절하는데도움이되는것이밝혀졌다 [35, 36]. 다양한기전의 B세포차단에대한임상연구가진행되고있다. Rituximab은 B세포표면에높게발현되는지단백인 CD20을표적으로하는쥐 / 인간키메라단클론항체이다. 1998년비호지킨임파종에사용이허가되어많은임상경험이축적되어있으며류마티스관절염의치료제로는 2001년경에처음시도되어효과가있음이증명되었다. 대규모임상시험을통해메토트렉세이트를비롯한항류마티스약물이나종양괴사인자차단제에효과가없는활동성류마티스관절염환자에서대조군에비해 ACR50, ACR70 반응이유의하게더높고관절파괴의억제효과가있으며, 이런효과는류마티스인자나항 CCP항체가양성인환자에서더높은것으로밝혀졌다 [37, 38]. 500 mg을 2주간격으로두번정맥주사하며주사반응을줄이기위해부신피질호르몬제
72 Hanyang Medical Reviews Vol. 32, No. 2, 2012 제를같이주사한다. Ocrelizumab과 Ofatumumab은 Rituximab과달리인간화된항CD20 단클론항체이며 CD20 분자의다른세포외항원결정인자에결합한다. 종양괴사인자차단제에효과가없는류마티스관절염환자에서임상시험중에있다 [39, 40]. 쇼그렌증후군에서효과를보였던인간화항CD22 단클론항체인 Epratuzumab 에대한연구가계획중에있다. B세포차단제가류마티스관절염치료에효과적임이밝혀진후다른경로의 B세포억제제들이연구되었다. B-lymphocyte stimulator (BLyS) 와 A PRoloferation-Inducing Ligand (APRIL) 는 B세포성숙과분화및기능에작용하는시토카인으로 B세포수용체인 TACI, BCMA, BAFF 수용체와결합한다 [41]. Atacicept (TACI 면역글로불린 ) 은인간면역글로불린 G1의 Fc영역과 TACI의결합체로 B세포수용체에 BLyS나 APRIL이결합하는것을막는다. 류마티스관절염환자에서 Rituximab과병용요법으로투여되는임상시험이진행되고있다 [42]. 7. Tyrosine kinase 억제제인산화에의해신호전달을하는세포내물질인단백질 kinase억제제들이새로운류마티스관절염의치료제로연구되고있다. Spleen tyrosine kinase (Syk) 는 B세포와여러 Fc-활성화수용체를표현하는세포에서중요한면역수용체신호전달물질이며, 이것이활성화됨으로써류마티스활막세포에서종양괴사인자를비롯한기질분해효소 (matrix metalloproteinase, MMP) 의생성을자극하게된다 [43]. Fostamitinib disodium (R788) 은전구물질로선택적 Syk억제제인 R406으로전환된다. 메토트렉세이트에반응하지않는환자들을대상으로한임상시험에서 IL-6, MMP-3의감소와함께 ACR50, ACR70반응이위약군에비해의미있게높았다. JAK3와 signal transducer and activator of transcription (STAT) 은특정시토카인수용체로부터면역세포의핵안으로신호전달에중요한역할을한다. 대규모 2상 /3상시험을통해 JAK3억제제 (CP-690, 550, Tasocitinib) 가메토트렉세이트와종양괴사인자차단제에효과를보이지않는류마티스관절염환자에서 24개월까지질병활성도의감소시키는것으로나타났다 [44]. 경구제제이며우리나라에서도현재 대규모임상시험이수행중에있다. Mitogen-activated protein kinase (MAPK) 는유전자전사를자극하는세포내분자로서 extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38 MAPK 의 3가지형태가있다. 그중 p38 MAPK이염증성시토카인생성에중요한역할을하는것으로알려져있으며선택적 p38 MAPK 억제제 (SCIO-460/Pamapinod/VX-702) 가임상시험을거쳤으나메토트렉세이트군에비해높은 ACR20 반응을보이지못했다. 또다른 Dual action MAPK 억제제인 BMS-582949도임상시험에서마찬가지로좋은결과를보이지못했다. 8. Denosumab ( 항RANKL 단클론항체 ) Receptor activator of nuclear factor kappa B ligand (RANKL) 에대한단클론항체인 Denosumab 은파골세포활성화를억제함으로써골파괴를막는다. 폐경후골다공증의치료제로먼저임상시험이시행되어좋은효과를보였다. 류마티스관절염환자에서도메토트렉세이트에병용요법으로 2상시험이진행되어자기공명영상으로확인되는골파괴를억제하는것으로나타났으나환자의임상증상을호전시키는데는불충분한효과를보였다 [45]. 9. BT-061 (Treg activating agonistic 단클론항체 ) Treg이정상면역체계유지에중요하며많은자가면역질환에서 Treg의양적, 질적인이상이보고되고있다. 최근인간화된 Treg활성화단클론항체인 BT-061을이용한 2상임상시험이류마티스관절염환자를대상으로행해졌다. 10. Granulocyte colony-stimulating factor (G-CSF), granu - locyte-macrophage colony-stimulating factor (GM-CSF) G-CSF와 GM-CSF는조혈, 특히골수계세포의생성, 분화및활성화에중요한역할을하는것으로알려져있으며, 자가면역질환에서이런성장인자들이증가되어있음이알려졌다. 현재이성장인자들에대한억제제가연구중이다.
73 11. Biosimilar 약제 References 2004년부터 2007년까지상위 8개생물학적약제 (Adalimumab, Lantus, Herceptin, Neulasta, Bevacizumab, Etanercept, Rituximab, insulin) 의매출이 250% 이상증가하면서의료비증가부담으로작용하였고, 상당수생물학적약제들의특허가끝남에따라동등한효과와안정성을가지는 Biosimilar 약제를개발할필요성이대두되었다 [46]. 화학약품들과달리크고복잡한 3차원구조의분자를제조하는데는적절한설비와기술이필요하며식품의약품안정청의지침에따라제조와약효동등성을담보하기위한국내임상시험을수행중이다. 결론최근 20여년간류마티스관절염의병리기전에대한면역학적, 분자생물학적이해가급속도로발전하고, 치료의패러다임에있어조기에고위험군을대상으로효과적이고강력한치료를하는쪽으로의변화가있었다. 이에본종설에서는이미상용화되어국내에서도활발하게사용되고있는각종염증성시토카인 ( 종양괴사인자, IL1, IL6) 과 B세포차단제, 이차신호차단제와더불어, 새로운치료표적으로서의효과에대해임상연구가수행되고있는 spleen tyrosine kinase와 p38 mitogen-activated protein kinase와같은세포내물질차단제, Treg차단제, RANKL차단제등의다양한종류의생물학적제제에대해기술하였다. 이렇게많은병인관련후보물질에대한표적치료가개발됨에따라, 약제들에대한비용-효과분석, 감염, 악성종양등의약제관련부작용문제에대한연구가더많이이루어져, 적절한비용과최소한의부작용으로류마티스관절염에대한효과적인치료가행해져야할것으로생각된다. 향후에는병인에대한보다깊은이해와함께발달된생물학공법에힘입어다양한병인을가지는류마티스관절염의표적치료가좀더결실을맺을수있을것으로기대한다. 1. Schenkier S, Golbus J. Treatment of rheumatoid arthritis. New thoughts on the classic pyramid approach. Postgrad Med 1992;91:289-92. 2. Wilske KR. Inverting the therapeutic pyramid: observations and recommendations on new directions in rheumatoid arthritis therapy based on the author s experience. Semin Arthritis Rheum 1993;23:11-8. 3. Buch MH, Emery P. New therapies in the management of rheumatoid arthritis. Curr Opin Rheumatol 2011;23:245-51. 4. van Vollenhoven RF. Treatment of rheumatoid arthritis: state of the art 2009. Nat Rev Rheumatol 2009;5:531-41. 5. Maini RN, Feldmann M. Cytokine therapy in rheumatoid arthritis. Lancet 1996;348:824-5. 6. Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell 1996;85:307-10. 7. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;365:2205-19. 8. Rigby WF. Drug insight: different mechanisms of action of tumor necrosis factor antagonists-passive-aggressive behavior? Nat Clin Pract Rheumatol 2007;3:227-33. 9. Knight DM, Trinh H, Le J, Siegel S, Shealy D, McDonough M, et al. Construction and initial characterization of a mouse-human chimeric anti-tnf antibody. Mol Immunol 1993;30:1443-53. 10. Kornbluth A. Infliximab approved for use in Crohn s dis ease: a report on the FDA GI Advisory Committee conference. Inflamm Bowel Dis 1998;4:328-9. 11. 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;354:1932-9. 12. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;43:1594-
74 Hanyang Medical Reviews Vol. 32, No. 2, 2012 602. 13. Etanercept. Soluble tumour necrosis factor receptor, TNF receptor fusion protein, TNFR-Fc, TNR 001, Enbrel. Drugs R D 1999;1:258-61. 14. Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arth ritis: double-blind randomised controlled trial. Lancet 2004;363: 675-81. 15. van der Heijde D, Klareskog L, Singh A, Tornero J, Melo- Gomes J, Codreanu C, et al. Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the TEMPO trial. Ann Rheum Dis 2006;65:328-34. 16. van Riel PL, Freundlich B, MacPeek D, Pedersen R, Foehl JR, Singh A. Patient-reported health outcomes in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial. Ann Rheum Dis 2008;67:1104-10. 17. 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;48:35-45. 18. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006; 54:26-37. 19. Keystone E, Heijde D, Mason D, Jr., Landewe R, Vollenhoven RV, Combe B, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, pla cebocontrolled, parallel-group study. Arthritis Rheum 2008;58: 3319-29. 20. Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall ST, Miranda PC, et al. Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009;68:789-96. 21. Smolen JS, Kay J, Doyle MK, Landewe R, Matteson EL, Wollenhaupt J, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 2009;374:210-21. 22. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-fourweek, multicenter, randomized, double-blind, placebocontrolled trial. Arthritis Rheum 2002;46:614-24. 23. Furst DE, Keystone EC, Kirkham B, Kavanaugh A, Fleischmann R, Mease P, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2008. Ann Rheum Dis 2008;67 Suppl 3:iii2-25. 24. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007;7:429-42. 25. Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006;54:2817-29. 26. Radin AR, Mellis SJ, Jasson M, Nadler D, Belomestnov P, Wu R, et al. REGN88/SAR153191, a fully-human interleukin-6 receptor monoclonal antibody, reduces acute phase reactants in patients with rheumatoid arthritis: preliminary observations from phase 1 studies. Arthritis Rheum 2010;62 Suppl 10:1121. 27. Mease P, Strand V, Shalamberdize L. Inhibition of IL-6 with ALD518 improves disease activity in rheumatoid arthritis in a randomized, double-blind, placebo-controlled, dose
75 ranging phase 2 clinical trial. Ann Rheum Dis 2010;69:98. 28. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin- 17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2010;2:52ra72. 29. Rheumatology 2010 annual scientific meeting. Secukinumab (AIN457), a novel monoclonal antibody targeting IL-17A demonstrates efficacy in active rheumatoid arthritis patients despite stable methotrexate treatment: results of a phase IIb study. Arthritis Rheum 2010;62:L9. 30. Gizinski AM, Fox DA, Sarkar S. Pharmacotherapy: concepts of pathogenesis and emerging treatments. Co-stimulation and T cells as therapeutic targets. Best Pract Res Clin Rheumatol 2010;24:463-77. 31. Westhovens R, Robles M, Ximenes AC, Nayiager S, Wollenhaupt J, Durez P, et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis 2009;68:1870-7. 32. Bathon J, Robles M, Ximenes AC, Nayiager S, Wollenhaupt J, Durez P, et al. Sustained disease remission and inhibition of radiographic progression in methotrexate-naive patients with rheumatoid arthritis and poor prognostic factors treated with abatacept: 2-year outcomes. Ann Rheum Dis 2011;70: 1949-56. 33. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144:865-76. 34. Schiff M, Pritchard C, Huffstutter JE, Rodriguez-Valverde V, Durez P, Zhou X, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis 2009;68:1708-14. 35. Cohen SB. Targeting the B cell in rheumatoid arthritis. Best Pract Res Clin Rheumatol 2010;24:553-63. 36. Edwards JC, Cambridge G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol 2006;6:394-403. 37. Edwards JC, Szczepanski L, Szechinski J, Filipowicz- Sosnowska A, Emery P, Close DR, et al. Efficacy of B-celltargeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81. 38. Cohen SB, Keystone E, Genovese MC, Emery P, Peterfy C, Tak PP, et al. Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate. Ann Rheum Dis 2010;69:1158-61. 39. Genovese MC, Kaine JL, Lowenstein MB, Del Giudice J, Baldassare A, Schechtman J, et al. Ocrelizumab, a humanized anti-cd20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study. Arthritis Rheum 2008;58:2652-61. 40. Taylor PC, Quattrocchi E, Mallett S, Kurrasch R, Petersen J, Chang DJ. Ofatumumab, a fully human anti-cd20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial. Ann Rheum Dis 2011;70:2119-25. 41. Calero I, Nieto JA, Sanz I. B cell therapies for rheumatoid arthritis: beyond B cell depletion. Rheum Dis Clin North Am 2010;36:325-43. 42. Tak PP, Thurlings RM, Rossier C, Nestorov I, Dimic A, Mircetic V, et al. Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, double-blind, placebocontrolled, dose-escalating, single- and repeated-dose study. Arthritis Rheum 2008;58:61-72. 43. Cha HS, Boyle DL, Inoue T, Schoot R, Tak PP, Pine P, et al. A novel spleen tyrosine kinase inhibitor blocks c-jun N-terminal kinase-mediated gene expression in synoviocytes. J Pharmacol Exp Ther 2006;317:571-8. 44. Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009;60:1895-905. 45. Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp
76 Hanyang Medical Reviews Vol. 32, No. 2, 2012 JT, et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheu matoidarthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum 2008;58:1299-309. 46. Suh SK, Park Y. Regulatory guideline for biosimilar products in Korea. Biologicals 2011;39:336-8.