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1 ISSN Journal of Multiple Sclerosis 6(2):23-28, 2015 REVIEW ARTICLE 다발성경화증치료의목표로서의질병무활성증거 영남대학교의과대학신경과학교실 빈창훈박민수 No Evidence Disease Activity as a Treatment Target in Multiple Sclerosis Chang Hun Bin, MD, Min Su Park, MD Department of Neurology, Yeungnam University College of Medicine, Daegu, Korea ABSTRACT No evidence of disease activity (NEDA) in multiple sclerosis (MS) means no relapse, no disability progression, and no new or enlarging lesions on MRI. NEDA is the treatment target in many inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Now, aggressive early disease modifying therapy is acceptable for treatment of MS to prevent the irreversible damage that leads to disability. As new and more effective therapies for MS become available, the treatment paradigm of MS can be expected to shift, such that NEDA or freedom of disease activity and NEDA is becoming an important measure in clinical trials. NEDA is an important goal for treating MS and a decision method of switching disease modifying therapy. There are many unsolved problems in NEDA and definition of NEDA would be changing by further new technologies and studies. Journal of Multiple Sclerosis 6(2):23-28, 2015 Key Words: No evidence of disease activity, Disease free state, Multiple sclerosis 서론 다발성경화증은중추신경계의만성적인자가면역성염증성탈수초성질환으로, 재발과완화를반복하거나진행성경과를보인다. 1 다발성경화증은재발이반복되면서완전히호전되지않고장애가남는다. 따라서초기에치료를시작해재발을줄여환자의예후를좋게하는것이중요하며, 이를위해서는정확한진단과효과적인치료제가필요하다. 2,3 신경면역학과병태생리학적이해와 MRI 기술의향상은다발성경화증의진단에많은발전을가져왔고, 이에맞추어질병조절치료 (disease modifying therapy, DMT) 가발전되었다. DMT 는다발성경화증의재발과장애의진행을줄이기위해사용되며, 최근까지작용기전과사용법이다른다양한약제들이개발되었다. 4,5 DMT 에대한과거연구들에서약제의효과는대부분연간재발률, 장애상태척도 (expanded disability status scales, EDSS) 와 MRI의변화여부로평가되었으며, 이러한척도들의수치를감소시키는, 다시말해질병의활성도를줄이는것이치료의목표였다. 하지만진단기술과치료제의발전은다발성경화증치료의개념을바꾸고있으며, 재발과장애진행을줄이는것을넘어최근에는무질병상태 (disease-free state) 나질병무활성증거 (no evidence of disease activity, NEDA) 에대한개념이다발성경화증치료영역에서새롭게언급되고있다. Received September 4, 2015 / Revised September 9, 2015 / Accepted September 9, 2015 Address for correspondence: Min Su Park Department of Neurology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: , Fax: , minsupark@ynu.ac.kr Journal of Multiple Sclerosis Vol. 6, No. 2,

2 빈창훈박민수 본론 1. 질병무활성증거의개념과배경 1) 최적하반응 (suboptimal response) 의개념다발성경화증환자를치료하다보면치료에대한반응이만족스럽지못한경우가종종있으며, 이런경우에는 DMT 변경이필요하다 (Table 1). 4,6 하지만현재까지 DMT 의변경에대한충분한근거중심의자료나지침은부족하다. 치료에반응이좋지않은경우를최적하반응혹은치료실패 (treatment failure) 라고하며, 이는현재 DMT 변경의기준으로임상과연구에서사용되고있다. 일차제제로치료하다가약제를변경하게된이유를연구한보고에따르면, 재발 (40%), 장애의진행 (20%) 및 MRI 활성도 (12%) 가약제변경을결정하는주된요인이었으며, 7 현재까지발표된연구들에서도재발, 장애의정도및 MRI를최적하반응을반영하는기준으로삼고있다. Freedmann 등은일차제제를사용하는다발성경화증환자중치료전과비슷한재발을보이거나, MRI 에서지속적인활동성이확인되거나, 장애의악화가회복되지않는경우를최적하반응으로판단하 고약제를변경할것을권유하고있다. 8 하지만최적하반응에대한정의는아직까지해결해야할문제중하나이다. 최적하반응에대한적용하기쉽고많이사용중인기준은 Rio score이다. Rio score를살펴보면재발, 장애의정도및 MRI가포함된다. 1년에 1회이상의재발, 6개월에 1점이상 EDSS 점수의증가, T2나조영증강영상에서 3개이상의활성병변이존재하는것을기준으로삼았으며, 최근에는수정된 Rio score (modified Rio score) 가제시되었다 (Table 2). 9,10 2) 질병무활성증거의배경과개념 NEDA의개념은다른면역매개염증질환 (immune-mediated inflammatory disease, IMID) 에근간을두고있다. IMID 에는류마티스관절염, 크론병, 건선등이있으며다발성경화증도 IMID에속한다. 11 류마티스관절염의경우, TNF-α antagonist가기존의항류마티스제제들 (gold, penicillamine, sulfasalazine) 보다높은관해율을보이게되면서 NEDA에대한생각을정립할수있게되었다. 12 다발성경화증도류마티스관절염처럼다양한종류의약제가개발되면서 NEDA 를치료의목표로삼기시작했다. 13 이에대한대표적인연 Table 1. Critical factors affecting the decision of changing current disease-modifying therapy for multiple sclerosis a first line DMT to another a first line to a second line DMT a second line DMT to another or to a third line DMT a second line to a first line DMT Tolerability/safety issues Suboptimal efficacy with disease activity not suitable for escalation to a second line DMT Persistent high-titre neutralizing antibodies in patients treated with interferon beta RR MS patients experiencing at least one relapse and with an active MRI during the previous year on treatment RR MS patients transitioning to the secondary progressive phase with evidence of relapses or MRI activity RR MS patients continuing to experience relapses Progressive forms of MS with relapses and/or active MRI despite treatment Safety issues (e.g., patients on natalizumab at high risk of developing progressive multifocal leukoencephalopathy) Tolerability/safety issues Risk perception of patient DMT: Disease-modifying therapy; RR: Relapsing-remitting; MS: Multiple sclerosis. Adapted from World Journal of Clinical Cases 2015;3: Table 2. Rio and Modified Rio Score Rio Score Modified Rio Score Criterion Change over the first year Criterion Change over the first year MRI criterion=0 MRI criterion=1 Relapse criterion=0 Relapse criterion=1 EDSS criterion=0 EDSS criterion=1 2 activet2 lesions >2 activet2 lesions No relapses 1 relapse Increase in EDSS score of <1 point Increase in EDSS score of 1 point, sustained over at least 6 months Rio score=mri criterion+relapse criterion+edss criterion EDSS: Expanded Disability Status Scale, MRI: magnetic resonance imaging. Adapted from Nature Reviews Neurology 2013;9: MRI criterion=0 MRI criterion=1 Relapse criterion=0 Relapse criterion=1 Relapse criterion=2 Not included 4 (5) newt2 lesions >4 (5) newt2 lesions No relapses 1 relapse 2 relapses Not included Modified Rio Score=MRI criterion+relapse criterion 24 대한다발성경화증학회지제 6 권제 2 호, 2015

3 다발성경화증치료의목표로서의질병무활성증거 구로 AFFRIM (a retrospective analysis of the natalizumab safety and efficacy in relapsing-remitting multiple sclerosis) 연구를들수있으며, 2년간의관찰기간동안위약군에비해 natalizumab 군에서임상적그리고영상학적으로무질병상태를보이는확률이 5배이상높았다고보고하였다 (37% vs 7%, p < ). 14,15 이처럼 NEDA는다발성경화증의연구나치료의목표가되어가고있다. NEDA는무질병상태 (disease-free state) 라는다른용어로도사용되지만, 아직까지다발성경화증의완전한질병활성도에대한평가는제한적이므로무질병상태는이상적인개념일수있다. 치료를통해 NEDA를만족시키는것은무질병상태를이루기위한과정이지만, 현재 NEDA에대한개념은무질병상태의다른표현이라기보다는최적하반응에대한평가의측면으로사용되는용어라고이해해야한다. 2. 질병무활성증거의기준최적하반응에대한기준과마찬가지로아직까지 NEDA 에대한기준도확실히정립되지않은상태이지만, 다양한연구에서 NEDA 를결과의한척도로사용하고있다 결국에는 NEDA와최적하반응은모두치료에대한평가의척도와치료제변경의근거로이용된다. Gold 등 19 은 best possible NEDA 라는개념으로약제변경에대한기준을제시하였으며, 그기준에는최적하반응에서언급한것처럼재발, 장애의정도와 MRI를포함하고있다 (Table 3). 여러연구에서사용한 NEDA의기준도 Gold 등의기준과비슷하며, 다음과같은항목을기준으로하고있다. 1 No new or enlarging T2-weighted lesions 2 No new gadolinium-enhancing lesions on MRI 3 No confirmed worsening of EDSS score 4 No clinical relapse 3. NEDA 에대한최근제안된기준 : Multiple Sclerosis Decision Model 최근 Stangel 등은신경정신적인부분, 개인적인업무 (working) 능력과삶의질적인측면을기존에사용하고있던 NEDA의기준에포함하여야한다고주장하며 4가지영역으로구성된 multiple sclerosis decision model (MSDM) 을제안했다 (Table 4). 20 4가지영역은재발 (relapses), 장애의진행 (progression of disability), 신경정신적인측면 (neuropsychology) 그리고 MRI를포함하고있으며, 각영역별로신호등처럼초록, 노랑, 빨강으로등급을나눈다. 4개의영역모두초록이면치료변경없이 6개월후재평가, 1개의영역이노랑이면 3개월이내에재평가, 2개이상노랑또는 1개이상빨강일때는치료의변경을권유하고있다. MSDM 이기존의기준과다른점은신경정신적인측면과장애척도로 EDSS 가아닌다른간단한척도를사용하고있다는점이며, 이에대한이유도언급하고있다. 신경정신적인측면은재발과장애의진행과같은신체적인측면외에인지기능, 피로나우울증과같은신경정신적인측면도다발성경화증환자의삶의질에중요한역할을하기때문에고려되어야한다. 장애의평가를위해간단한척도를사용한이유는 EDSS 점수가낮은경우에는장애의진행에대한평가가쉽지않아서미세한변화를발견할수있는민감한도구가필요하기때문이다. Table 3. Criteria that should be considered for the evaluation of clinically relevant and measurable NEDA in patients with relapsing remitting MS that should be considered for treatment adjustment Relapse activity The occurrence of one of the following events during therapy should in most cases result in a therapeutic change: 1 relapse with incomplete remission 1 severe relapse with necessity of escalating acute therapy [ultra high steroid treatment (i.e. 2 g/day for 5 days) or plasma exchange] 2 clinically objectified relapses without residual symptoms in 1 year whenever possible, with evidence of a correspondingly localized lesion in the MRI Disability progression Depending on the individual patient situation, even slight impairments represent a significant impairment in the working ability and quality of life The EDSS value should categorically be kept under 3 for as long as possible However, the EDSS is not sensitive enough particularly in its lower ranges Fatigue and cognitive parameters are not considered enough in the EDSS MRI parameters The decision on treatment change should not be based solely on MRI findings The detection of multiple new or enlarged T2 lesions or gadolineum-enhancing inflammatory lesions can, however, serve as an additional criterion EDSS: Expanded Disability Status Scale, MRI: magnetic resonance imaging, MS: multiple sclerosis, NEDA: no evidence of disease activity. Adapted from Therapeutic Advences Neurological Disorders 2015; 8:3-13. Journal of Multiple Sclerosis Vol. 6, No. 2,

4 빈창훈박민수 Table 4. The multifactorial model: the domains of disease activity and their rating to assess disease progression and integrated interpretation of the multifactorial model Domains of disease activity MSDM points Interpretation of MSDM total score Relapse Each relapse 3 Characteristics 0 points=green Functionally relevant (individual evaluation: job, sports, etc.) +1 With residual symptoms after 3 to 6 months points=yellow Interval since start of treatment or last change of treatment >12 months +0 5 points=red 6-12 months +1 >3 to <6 months +2 Progression of disability (modified MSFC) T25FW, 9HPT, LCSLC (panel with 1.25% contrast) 0 points=green Each test with worsening by 20% 1 Each test with worsening by 40% 2 1 points=yellow SDMT Worsening by 4 points 1 2 points=red Worsening by 8 points 2 Neuropsychology Fatigue (FSMC) Worsening by 1 category 1 0 points=green Worsening by 2 categories 2 Worsening by 3 categories 3-2 points=yellow Depression (determined by HADS) -1 Anxiety (determined by HADS) -1 3 points=red Quality of life (MSIS-29) No MSDM points Change by >7 points Warning sign! Check up at short notice MRI findings 0-2 points=green Each Gd-enhancing lesion 1 Each new or enlarged T2 lesion without Gd enhancement 1 3 points=yellow Integrated Interpretation All domains green No changes in therapy. Reevaluate in 6 months 1 domain yellow Reevaluate in 3 months 2 domain yellow Consider optimization/change of therapy or 1 domain yellow or 9HPT-9, hole peg test; FSMC: fatigue scale for motor and cognitive functions, GD: gadolineum, HADS: hospital anxiety and depression scale, LCSLC: low contrast sloan letter chart, MS: multiple sclerosis decision model, MSFC: multiple sclerosis functional composite, MSIS-29: multiple sclerosis impact scale, T25FW: 25-foot walk. Adapted from Therapeutic Advences Neurological Disorders 2015;8: 대한다발성경화증학회지제 6 권제 2 호, 2015

5 다발성경화증치료의목표로서의질병무활성증거 4. 질병무활성증거의현재와미래 1) 질병무활성증거에대한최근연구 Rotstein 등 21 은다발성경화증환자들의 NEDA에대한평가를발표하였고, 7년간 219명의재발-완화다발성경화증환자를대상으로 6개월간격의진찰과 1년간격의 MRI를시행해서환자들의 NEDA 를분석했다. 첫 1년에는 46%, 2 년째는 27.5% 의환자가 NEDA 기준을만족했으나, 7년후에는단지 7.9% 의환자만이 NEDA 상태였다. NEDA의양성예측도는 4년째에가장높았고 (85%), 2년째 NEDA 기준을만족한환자들중 78.3% 는 7년후 EDSS의진행 (EDSS score change 0.5) 이없었다 (1년째는 71.7%). NEDA 는초기 ( 발병후 5년까지 ) 에더정확히예측이가능하며, 각각의척도보다전체적인 NEDA 평가가진행에대한예측을더잘할수있었다. 하지만치료를하고있음에도 NEDA 를장기간유지하는것은어렵다는것도알게되었다. 앞서언급했던척도들외에도 NEDA의기준으로삼을수있는다른척도에대한연구도진행되고있다. 다발성경화증환자의 MRI에서관찰되는 T1 영상에서의지속적인저신호강도의병변 (black hole) 이나대뇌피질의변화도기준으로가능성이있으며, 이들은장애의정도와연관성이있어 NEDA 척도가될수있다. 22 2) 질병무활성증거에서해결해야될문제들 NEDA는재발성질환의치료에대한목표이며앞으로이루어질많은임상연구에서결과의척도로이용될것이다. 하지만 NEDA에대한기준외에도 NEDA에대한기준이현재사용되는기준으로충분한지, NEDA가유지되는기간은어느정도여야하는지, NEDA에대한평가는어느정도시간적간격을두고확인해야하는지, 또한약제변경에대한 NEDA나최적하반응의역할등해결해야할많은질문들이남아있다. MRI 측면을보면, 언제 MRI를시행해야하는지에대해고민을해야한다. Giovannoni 등 23 은 DMT의치료효과가나오고나서 MRI를시행할것을제안했다. 23 DMT를시작한지얼마지나지않았을때의질병활성도는평가되지않아야한다. 구체적으로, interferonbeta, teriflunomide, dimethyl fumarate와 natalizumab 은 3-6개월, glatiramer acetate는 9-12개월, 그리고 alemtuzumab 은마지막코스 12개월이나첫시작 24개월후에 MRI를시행하도록추천하고있다. 또다른고민은뚜렷한재발이없이진행하는환자에있어서 DMT를변경해야하는지에대한것이며, 재발이없는장애의진행도 NEDA의기준에넣어야할지에대한논란이있다. 또한현재의 NEDA의기준도질병활성도를평가할수 있는완전한방법은아니다. 현실적으로정확한질병활성도는평가할수없을지도모른다. 따라서현재사용중인척도외에환자- 연관결과측정 (patient-related outcome measure), 회백질과연관된질병활성도와신경미세섬유 (neurofilament) 와같은생물지표 (biomarker) 등과같은다양한척도에대한연구가필요하다. 결론 치료제의효과가높아지고, 선택할수있는치료제들이다양해지면서다른 IMID처럼다발성경화증도 NEDA라는개념이언급되고있다. 다양한임상연구들에서도 NEDA 를결과의한척도로사용하고있으며, NEDA에의해치료효과에대한판정이더정확해질수있다. 하지만 NEDA 는환자의평가를위해아직까지완벽한기준은아니다. 새로운기술과연구를통한 NEDA 기준의발전은치료반응에대한평가의정확도를높여줄것이므로 NEDA에만족하지않고무질병상태를이루기위해서많은노력을해야할것이다. ACKNOWLEDGEMENTS This article is written based on the manuscript of The Window of Multiple Sclerosis Volume 8 Number 1. REFERENCES 1. Weinshenker BG. The natural history of multiple sclerosis. Neurologic Clinics 1995;13: Kim WJ, Kim HJ. Multiple Sclerosis. J Korean Med Assoc 2009; 52: Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Millter DH, et al. 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: Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: when to start, when to change, when to stop? World J Clin Cases 2015;3: Goodin D, Frohman E, Garmany G. 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: Karussis D, Biermann LD, Bohlega S, Boiko A, Chofflon M, Fazekas F, et al. A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting. Eur J Neurol 2006;13: Gajofatto A, Bacchetti P, Grimes B, High A, Waubant E. Switching Journal of Multiple Sclerosis Vol. 6, No. 2,

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The Window of Multiple Sclerosis

THE WINDOW OF MULTIPLE SCLEROSIS Vol.2 No.1 MAR 2009 Topic Review Article Review 01. 02. 03. 04. Case Review The Window of Multiple Sclerosis THE WINDOW OF MULTIPLE SCLEROSIS The Window of Multiple Sclerosis