ISSN 2093-2952 Journal of Multiple Sclerosis 1(1):6-11, 2010 REVIEW ARTICLE 가톨릭대학교의과대학신경과학교실 안재영이광수 Recent Clinical Trials of Multiple Sclerosis Jae Young An, MD, Kwang Soo Lee, MD, PhD Department of Neurology, The Catholic University of Korea College of Medicine, Seoul, Korea ABSTRACT The immunopathogenesis of multiple sclerosis has been broadened during the past decade and a number of new strategies were developed for the treatment of the disease. Six pharmacological agents are currently approved for the treatment of multiple sclerosis. However, these drugs are only partially effective and patients may still encounter relapses, disease progression or adverse effects. A sizable number of new agents and optimizing current therapies such as various combination regimens are under investigation currently. However, with availability of newer therapies, the choice of a first-line agent will become more complicated with risk-to-benefit ratios playing a major role in the decision making process. Journal of Multiple Sclerosis 1(1):6-11, 2010 Key Words: Multiple sclerosis, interferon-β, glatiramer acetate, cladribine, fingolimod, monoclonal antibody 서론 다발성경화증 (multiple sclerosis; MS) 은중추신경계의만성염증성질환으로, 정확한병인은모르지만유전적성향, 환경적유발요인과면역조절곤란과관련한면역관용의파괴로인한것으로알려져있다. 1 MS의면역발병기전의이해가높아지면서 MS 치료의임상연구에도많은발전이있었다. 현재까지재발이장성다발성경화증 (Relapse-remitting Multiple sclerosis; RRMS) 의치료제로승인을받고있는것은 6가지약제이다. 일차치료제로 INF β-1a: 피하 (s.c.) (Rebif ), 근내주사 (i.m.) (Avonex ), INFβ-1b (s.c.) (Betaferon /Betaseron ), glatiramer acetate (Copaxone ) 가있다. 일차약제는치료효과와안정성, 관용성이주요임상연구와시판후임상경험으로입증되어있다. 이차약제로는 natalizumab (Tysabri ), mitoxantrone (Novantrone ) 이 있다. 이차약제는좀더강력하고비교적좋은관용성을보이고있지만, 안정성문제로인해서이차약제로고려되고있다. 최근 1년간 MS와관련하여학회와저널에서발표된연구결과를통해새로운 MS 치료제와기존약제의부작용및새로운치료전략에대해알아보고자한다. 본론 1. 임상적독립증후군 (Clinical isolated syndrome; CIS) 치료 현재 CIS의치료에서는임상적으로확실한 MS (clinical definite multiple sclerosis; CDMS) 로진행하는것을늦추기위해서가급적조기에약물치료를시작하는것으로치료지침을삼고있다 (Level A guideline). 2 CHAMPS (Controlled Received December 29, 2009 / Accepted January 25, 2010 Address for correspondence: Kwang Soo Lee, MD, PhD Department of Neurology, Kangnam St. Mary Hospital, 505 Banpo-dong, Seocho-gu, Seoul, 137-070, Korea Tel: +82-2-590-2091, Fax: +82-2-599-9686, E-mail: ks1007@catholic.ac.kr 6 대한다발성경화증학회지제 1 권제 1 호, 2010
High Risk subjects Avonex Multiple Sclerosis Prevention Study) 연구 3 를통해 Avonex 가, BENEFIT (Betaseron in Newly Emerging MS For Initial Treatment) 연구 4 를통해 Betaserone 이각각 CIS 치료제로서 FDA 승인을받았다. Rebif 는 FDA 승인은받지못했지만 ETOMS (Early Treatment of MS) 연구를통해효과가입증되었다. 5 하지만이임상시험에서는전체환자중 39% 가다발성증상을갖고있었다. Glatiramer acetate (GA) 의 CIS에대한연구인 PreCISe 의중간결과가 2008년 AAN (America Academy of Neurology) 과 WCTRIMS (World congress on treatment and research in multiple sclerosis) 에발표되었고최근발행되었다. 6 총 481 명의 CIS 환자를대상으로 36개월간의연구기간동안위약군과 GA 군 (20 mg/day) 을비교한결과위약군에비해 45% 정도 CDMS 으로의진행위험을낮추는것으로나타났다 (25% vs 45%, p<0.0001). MS로의진행시간이나 (722 days vs 336 days, p<0.0005), MRI 상병변의수도현저히차이가나서안정성문제로이중맹검위상을중단하고모든환자를적극적치료군으로포함시켰으며, 2009년 CIS 치료약제로미국과유럽에서승인을받았다. 최근인터페론의조기치료장기효과에대한연구결과발표도있었다. Benefit 연구의 3년간추적연구 7 에이어 5 년간추적연구결과가최근에발표되었다. 8 이연구에서는조기에치료한 CIS 환자군이치료지연군에비해 CDMS 로전환위험도가적었으며 (46% vs 57%, p=0.003), 재발률 (0.21 vs 0.27, p=0.014) 과새로운활동성 MRI 병변 (p=0.0062) 에서도조기치료군이좋은임상결과를보였다. 2009년 AAN에서는 CHAMPIONS (Controlled High- Risk AVONEX (interferon beta-1a) Multiple Sclerosis (MS) Prevention Study In Ongoing Neurologic Surveillance) 5-year 연구 9 에이어 10년간의추적연구가발표되었다. 10 이연구에서도마찬가지로 CIS 후즉시치료를시작하는군이치료지연군에비해 40% 에서평균 30개월가량 CDMS 로전환하는시기를연장하는것으로나타나고, Avonex 치료를한군의 80% 가 10년후에도 EDSS socre가 3 이하로유지하는결과를보였다. CIS 치료를가급적빨리시작하는것이장기적인예후에도영향을미친다는연구결과들이지속적으로나오고있다. 2. 단클론항체 (monoclonal antibody) Natalizumab (Tysabri ) 은 VLA-4에대한인간단클론항체 (humanized monoclonal antibody) 로두개의무작위이중 맹검위약대조군연구인 AFFIRM (A randomized placebocontrolled trial of natalizumab for relapsing multiple sclerosis) 11 과 SENTINEL (safety and efficacy of natalizumab in combination with interferon ß-1a in patients with relapsing remitting MS) 12 로 2004년 FDA 승인을받았으나, 2005년에 MS 환자에서 2명, 13,14 Crohn s disease 에서 1명 15 등총 3명의다초점백색질뇌증 (progressive multifocal leukoencephalopathy; PML) 환자가보고되면서시장에서자발적으로철수하였다. 이후임상연구를통해 3,000여명의환자에서기존 3명이외엔보고가없어 PML 위험은대략 1/1,000명정도로보고 16 가되어다시시장에진입한약제이다. 2009 년 AAN에서 natalizumab 의안정성평가를위한세계위험관리프로그램인 TOUCH (Tysabri Outreach: Unified Commitment to Health) 처방프로그램과 TYGRIS (Tysabri Global Observation Program in Safety) 프로그램에서얻어진자료를분석발표하였다. 17 재승인이후약 3년동안미국과유럽에서대략 52,000명의환자중에서 6예의 PML 이보고되어위험성이 1.2/10,000명정도로기존의발표보다더낮은수치를보고하였으나, 그이후에 natalizumab 의사용기간과환자수가늘어나면서 PML 환자도지속적으로보고되어 2009년 10월까지 24명의확진된 PML 환자가보고되고있어추후계속적인감시가필요할것으로생각된다. 18 Rituximab (Rituxan ) 은 CD20 에대한단클론항체 (chimeric murine/human monoclonal antibody) 로정주 rituximab은선택적으로 B 림프구고갈을유발하는작용을가진다. 이미비호지킨림프종과류마티스관절염에승인을받은약제이다. 104명의 RRMS 환자를대상으로 1년간추적기간을가지고위약과비교한제2상임상연구결과에서는 rituximab 군이일차결과 (primary outcome) 인 MRI상총조영증강병변수에서유의한차이를보였다. 19 하지만, rituximab을사용한환자군중 24.6% (16/65) 가항키메라항체 (antichimeric antibody) 가발견되었다. 이항체가 rituximab 의부작용이나, 효과적인측면에서직접적인연관이있는지는증명되지않았지만, 반복적인투여에있어서는문제가될수있어최근에인간화항체 (humanized anti-cd20 monoclonal antibody) 인 Ocrelizumab 이란약제가 RRMS 환자에게위약과 INF β-1a (i.m.) 등세군과의제2상임상연구가현재진행중에있다 (http://clinicaltrials.gov). 최근 rituximab 의 439명의원발성진행형다발성경화증 (primary progressive MS; PPMS) 에관한제2/3상임상연구결과가발표되었다. 20 일차결과인 2년내미리정의된질병진행까지의시간은위약군과차이가없는결과를보였지만, 아형분석에서 51세이하의환자와 MRI상조영증강병변 Journal of Multiple Sclerosis Vol. 1, No. 1, 2010 7
안재영이광수 에서는통계적으로유의한차이가있어향후 PPMS 환자의임상연구계획에도움을준연구라할수있겠다. Alemtuzumab (COMPATH-1H) 은 CD52 항원에결합하는단클론항체 (humanized monoclonal antibody) 로 B 세포만성림프성백혈병에승인을받은약제이다. 제2상임상연구 21 를통해 alemtuzumab 이지속적인장애의진행속도를감소시키고, 무재발환자비율이나, T2 강조 MRI 영상의고신호병변에서도유의한이점을보였다. 하지만, 갑상선질환, 면역혈소판감소성자반증 (immune thrombocytopenia purpura) 과같은항체매개성자가면역질환이 alemtuzumab 군에서더흔한것으로보고되었다. 이후현재 Rebif 와비교연구, 제2상의연장연구 (extension study) 등 2개의제3상임상연구가진행중이다 (http://clinicaltrials.gov). 3. 세포독성치료제 (Cytotoxic agent) Mitoxantrone (Novantrone ) 은이차진행형다발성경화증 (secondary progressive MS) 과기존면역조정제에반응이없는활동적재발이장성다발성경화증 (worsening relapse remitting MS) 의치료에대해 2000년에 FDA 승인을받은면역억제제이다. 이약물의가장심한두가지합병증은심장독성과치료연관급성백혈병 (t-al) 이다. t-al 위험성은기존보고에따르면 0.07에서 0.25% 이지만, 22,23 이탈리아그룹에서 2,854명의 MS 환자를대상으로시행한연구결과실제그위험은더높다고 2009년 AAN에서발표했다. 24 최소한번이상의 mitoxantrone 치료를받았고, 최소 1년이상을관찰한환자들에서총 21명의백혈병이발생해기존보고보다더높은 0.74% 의발생률을보고했다. 저자들은실제 mitoxantrone을치료제로선택할경우지속적인혈액학적검사의중요성을강조했다. 4. 스테로이드병용요법 인터페론의 RRMS에대한치료효과는여전히부분적이어서좀더효과적이고새로운방법이시도되고있다. 그중하나로, 중화항체생성이고용량의 INF의치료에중요한장애가되고있어, 25 스테로이드의병용요법이인터페론의치료효과를더욱증가시킬수있다는가설아래최근몇가지연구결과가발표되었다. 2009년게재된 NORMINS (NORdic trial of Methylprednisolone as add-on therapy to Interferon-beta for treatment of relapsing-remitting Multiple Sclerosis) 연구 26 는 130명의환자를대상으로기존에 INF β -1a를맞고있는환자중재발이최소 1년에한번이상있는사람이메칠프레드니솔론을한달에한번씩 5일간 투여했을경우, 위약군과비교시재발률이통계적으로유의하게적었다 (0.22 vs 0.59, p<0.0001). 하지만이연구는적은수의환자와부작용등으로인한높은중도포기율 (26%) 의제한점이있었다. 같은시기에 2009년 AAN에서 MECOMBIN (Methylprednisolone in Combination With Interferon Beta-1a (Avonex )) 연구결과가발표되었다. 27 이전에 DMTs 로치료받은적이없는 341명의환자를대상으로매주 Avonex 치료를하면서매달경구메칠프레드니솔론군 (500 mg/day for 3 days) 과위약군을비교하였다. 이연구에서는 6개월이상의지속적진행을보이는시간으로하는일차결과에서는양군간의차이는없었지만, 이차, 삼차결과인기능성, 재발률, MRI 변화에서는통계적인차이를보였다. 이연구에서도높은중도포기율 ( 스테로이드 ; 52%, 위약 ; 38%) 을보여저자들은스테로이드병용요법을임상적인치료로제시할수는없지만스테로이드가효과적인병용치료가될수있다는점을주장했다. 5. 경구치료제 기존의 DMTs 들은주사약이라는투약방법때문에장기적인순응도에좋지않은영향을끼쳤다. 그래서순응도를증가시켜장기적인치료효과를높이는장점을가지는경구약제들은일차치료제로서높은가능성을가지고있다. 2009년한해동안있었던많은발표들가운데 Cladribine과 Fingolimod 두가지경구약제의긍정적제3 상임상연구결과가가장많은관심을받았다. 1) Cladribine Cladribine은탈아미노효소저항퓨린유사제 (adenosine deaminase-resistant purine analogue) 로서 CD4+T 세포를선택적으로고갈시키는작용을가진다. 28 이약제는이미모발상세포백혈병 (hairy cell leukemia) 과림프종에서인증을받은약제로비경구적 cladribine이 RRMS에서나, progressive MS에서효과를보인연구들은있었다. 28-31 2009 년 AAN에서발표된 cladribine 제3상연구인 CLARITY (Cladribine Tablets Treating MS Orally) 연구 32 는 1,326명의 RRMS 환자를대상으로 2년간추적기간으로, 고용량군 (5.25 mg/kg daily for four to five days, with 4 courses in the first year), 저용량군 (3.5 mg/kg daily for four to five days, with 2 courses in the first year; both treatment groups were given 2 treatment courses in the second year), 위약군으로나누어서진행한이중맹검연구이다. 일차결과인연중재발률은위약, 저용량, 고용량군이각각 0.33, 0.14 (p<0.001 vs placebo), 0.15 (p<0.001 vs placebo) 로나타났고, 이차결과 8 대한다발성경화증학회지제 1 권제 1 호, 2010
중하나인 2년시점에무재발환자비율은위약, 저용량, 고용량군이각기 60.9%, 79.7% (p<0.001 vs placebo), 78.9% (p<0.001 vs placebo) 로결과가나타났다. MRI상에서도위약군과 cladribine 을사용한군간에통계적으로유의한차이를보였다. 심각한부작용은위약군에서 6.4%, 저용량군에서 8.4%, 고용량군에서 9.0% 를보였으며, 백혈구감소증은 cladribine 치료군 (high dose; 31%, low dose; 22%, placebo; 2%) 에서더흔히나타났다. CLARITY 연구이외에도, CLARITY 연장연구, ORACLE-MS (Oral CLadribine for Early MS), ONWARD (Oral Cladribine Added On to Rebif New Formulation in Patient With Active Relapsing Disease) 가현재진행중에있다 (http://clinicaltrials.gov). 2) Fingolimod Fingolimod (FTY720) 는하루한번복용하는경구용면역조정약제로 sphingosine-1-phosphate (S1P) 의합성유사체이다. S1P 수용체를조정하여림프구를이차림프기관에격리시켜중추신경계로의진입을억제하는기전을가지고있다. Fingolimod와관련하여세가지제3상임상연구중하나인 TRANSFORMS 임상연구의결과가 2009년 AAN에서발표되었다. 33 이연구는두가지용량의경구 fingolimod와 Avonex 를비교하는직접비교임상연구로 1,292명의 RRMS 환자를대상으로 1년간진행되었다. 1년후시점에서무재발비율이 Avonex 군은 69% 인것에비해 Fingolimod 군은저용량, 고용량모든군에서 80~83% 정도로유의하게높은결과를보였고, 재발률도 fingolimod 군이 Avonex 군에비해저용량군은 52%, 고용량군에서는 38% 가적었다. 인플루엔자유사증상과우울증은 Avonex 군에서흔했지만, 심각한부작용은 fingolimod에서더흔했다. 헤르페스감염과관련된두건의사망이고용량 fingolimod 군에서관찰되었으며, 국소암이 Avonex 군의 2건에비해 8건의사례가 fingolimod 군에서보고되었다. TRANSFORMS 연구외에도 2년의기간으로진행되는무작위이중맹검연구인 FREEDOM (Fingolimod Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) 연구와 progressive MS 환자에서장애진행성지연에관한 INFORMS (FTY720 in patients With Primary Progressive Multiple Sclerosis) 연구가현재진행중에있다 (http://clinicaltrials.gov). 이두가지약제의긍정적인제3상임상연구결과로, 빠른시일내에경구용약제가 RRMS 의치료시장에진입할예정에있다. 3) 기타제2상, 2b상연구를통해위약군과비교해 MRI상유의 한차이를보였지만, 재발률에서는그러지못했던푸마르산 (Fumaric acid; BG-12) 34 과 laquinimod, 35 Teriflunomide 36 는현재대규모제3 상임상연구가진행중이다 (http://clinicaltrials.gov). 스타틴제제가실험연구를통해면역조절기능을가지고있다는결과를보인후, 37,38 소규모공개임상시험을통해서경구심바스타틴을투여한경우 MRI상에서조영증강병변이감소되는결과가나타나 RRMS에서스타틴의치료가능성을보였다. 이후인터페론과병용사용시인터페론신호전달의차단효과로인한대항효과가몇몇보고에서발표되었으나, 39,40 2007년 SIMCOMBIn (Simvastatin as an Add-on Treatment to Interferon-beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis) 연구의중간보고에서는대항효과는없는것으로발표되었다. 41 현재 CIS에서도인터페론과병용요법이안전한것으로예비연구에서발표되었고 42, CIS 의단일치료제로스타틴에관한연구가진행중이다 (http://clinicaltrials.gov). 결론 지난 10년간 MS에관해연구가활발히진행되면서임상적연구에반영되어다양한치료약제들이개발되어왔다. 새로운치료제의임상적연구뿐만아니라, 기존치료약들에관해서도다양한연구들이발표되고진행되고있다. MS 치료약제수가늘어나고있지만약제들의치료효과는아직부분적이며, 단기간의연구결과로인한부족한안정성에대한평가로인해임상에서일차치료약을결정하는것이더욱힘들어질것으로예상된다. MS 환자의치료를선택할때있어서각기치료약제들의유해유익비율 (risk to benefit ratio) 을충분히고려해야하고, MS 치료약제들의향후계속되는연구결과를지속적으로관심을가지고지켜봐야할것으로생각된다. REFERENCE 1. Bar-Or A. The immunology of multiple sclerosis. Semin Neurol 2008;28:29-45. 2. Goodin DS, Frohman EM, Garmany GP Jr, Halper J, Likosky WH, Lublin FD, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002;58(2):169-178. 3. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898-904. 4. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Journal of Multiple Sclerosis Vol. 1, No. 1, 2010 9
안재영이광수 Miller DH, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006;67:1242-1249. 5. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernández O, et al. Early Treatment of Multiple Sclerosis Study Group. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357:1576-1582. 6. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, et al. PreCISe study group. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009;374:1503-1511. 7. Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al. BENEFIT Study Group. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370:389-397. 8. Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al. BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 2009;8:987-997. 9. Kinkel RP, Kollman C, O Connor P, Murray TJ, Simon J, Arnold D, et al. CHAMPIONS Study Group. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006;66:678-684. 10. Kinkel RP, Tanner J, Simon J, O Connor P, Kollman C. CHAMPIONS Extension study: 10-year Follow-Up after a clinically isolated syndrome (CIs) in high risk patients. AAN meeting Abstract 2009 [P06.137]. 11. Polman CH, O Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al.; AFFIRM Investigators. A randomized placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899 910. 12. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al.; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911 923. 13. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369-374. 14. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-381. 15. Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn s disease. N Engl J Med 2005;353:362-368. 16. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354:924-933. 17. Bozic C, Belcher G, Kim R, Hyde R, Lynn F, Carmen B, et al. Natalizumab in patients with relapsing multiple sclerosis: Update utilization and safety results including TOUCH TM and TYGRIS. AAN meeting Abstract 2009 [S11.005]. 18. Tornatore C, Clifford DB. Clinical vigilance for progressive multifocal leukoencephalopathy in the context of natalizumab use. Mult Scler 2009;15(S4):S16-S25. 19. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358: 676-688. 20. Hawker K, O Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, et al. OLYMPUS trial group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009;66:460-471. 21. CAMMS223 Trial Investigators, Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359:1786-1801. 22. Ghalie RG, Mauch E, Edan G, Hartung HP, Gonsette RE, Eisenmann S, et al. A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 2002;8:441 445. 23. Capobianco M, Malucchi S, Ulisciani S, Fava C, Cambrin GR, Avonto L, et al. Acute myeloid leukemia induced by mitoxantrone treatment for aggressive multiple sclerosis. Neurol Sci 2008;29:185-187. 24. Martinelli V, Bellantonio P, Bergamaschi R, Bertolotto A, Cavalletti G, Cocco E, et al. Incidence of acute leukemia in multiple sclerosis patients treated with mitoxantrone: a multicenter retrospective study. AAN meeting Abstract 2009 [LB3.001]. 25. Sørensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, et al. EFNS Task Force on Anti-IFN-beta Antibodies in Multiple Sclerosis. Guidelines on use of anti-ifn-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005;12:817-827. 26. Sorensen PS, Mellgren SI, Svenningsson A, Elovaara I, Frederiksen JL, Beiske AG, et al. NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol 2009;8:519-529. 27. Ravnborg M, Soerensen PS, Andersson M, Celius EG, Elovaara I, Nijmegen PJ, et al. A multi-centre, double blind, randomized, placebo controlled, parallel group trial investigating methylprednisolone (MP) in combination with Interferon-b-1a for the treatment of relapsing-remitting multiple sclerosis (RRMS). AAN meeting Abstract 2009 [LB3.002]. 28. Beutler E, Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A 1996;93:1716-1720. 29. Brousil JA, Roberts RJ, Schlein AL. Cladribine: an investigational immunomodulatory agent for multiple sclerosis. Ann Pharmacother 2006;40:1814-1821. 30. Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J, Beutler E. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994;344:9-13. 31. Rice GPA, Filippi M, Comi G, Cladribine MRI Study Group. Cladribine and progressive MS. clinical and MRI outcomes of a multicenter controlled trial. Neurology 2000;54:1145-1155. 32. Giovannoni G, Comi G, Cook SD, Rammohan KW, Rieckmann 10 대한다발성경화증학회지제 1 권제 1 호, 2010
P, Sorensen PS, et al. Results from the CLARITY Study: a Phase III, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Oral Cladribine in Relapsing-Remitting Multiple Sclerosis (RRMS). AAN meeting Abstract 2009 [LBS. 001]. 33. Cohen J, Pelletier J, Kappos L, Montalban X, Hartung HP, Comi G, et al. Oral Fingolimod (FTY720) Versus Interferon Beta-1a in Relapsing-Remitting Multiple Sclerosis: Results from a Phase III Study (TRANSFORMS). AAN meeting Abstract 2009 [S21.004]. 34. Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, et al. BG-12 Phase IIb Study Investigators. BG-12 Phase IIb Study Investigators. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomized, double-blind, placebo-controlled phase IIb study. Lancet 2008;372:1463-1472. 35. Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, et al. LAQ/5062 Study Group. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008;371:2085-2092. 36. O Connor PW, Li D, Freedman MS, Bar-Or A, Rice GP, Confavreux C, et al. Teriflunomide Multiple Sclerosis Trial Group; University of British Columbia MS/MRI Research Group. A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006;66:894-900. 37. Greenwood J, Walters CE, Pryce G, Kanuga N, Beraud E, Baker D, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experiemental auto-immune encephalomyelitis. FASEB J 2003;17:905 907. 38. Youssef S, Stüve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, et al. The HMG-CoA reductase inhibitor atorvastatin, promotes loss of therapeutic effect of IFN-beta in multiple sclerosis. Neurology 2007;68(suppl 1):A364. 39. Dhawan N, Reder A. Statins block interferon signaling in human immune cells: potential loss of the therapeutic effect of IFN-beta in multiple sclerosis. Neurology 2007;68(suppl 1):A364. 40. Birnbaum G, Altafullah I, Reder A. A double blind, placebo controlled trial of atorvastatin in combination with subcutaneous interferon beta 1a in persons with multiple sclerosis. Neurology 2007;68(suppl 1):A206 A207. 41. Sorensen PS, Frederiksen JL, Lycke J, Sellebjerg F. Does Simvastatin antagonise the effect of interferon beta? Interim safety analysis of the ongoing SIMCOMBIN study. Mult Scler 2007;13:S25. Abstract. 42. Markovic-Plese S, Speer D, Jin J, Smrtka J, Ingram L, Jewells V. Statin and intramuscular interferon beta-1a combination therapy is safe and well tolerated in patients with clinical isolated syndrome suggestive of multiple sclerosis, a pilot study. Mult Scler 2007;13:S270. Abstract. Journal of Multiple Sclerosis Vol. 1, No. 1, 2010 11