대한건선학회지 Vol. 6, No. 1, 2009 고전적인국소치료제제의다양화 1. 국소스테로이드 (Topical corticosteroids) 스테로이드는효과가뛰어나며그효과가빠르게나타 난다는이점이있어현재까지도가장많이사용되는국 소치료제이다. 최근에는 clobetasol

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1 대한건선학회지제 6 권, 제 1 호 Journal of the Korean Society for Psoriasis Vol. 6, No. 1, 1-6, 2009 건선국소치료의최신지견 노효진 배병기 이주희 연세대학교의과대학피부과학교실및피부생물학연구소 Recent Advances in Topical Therapy of Psoriasis Hyo Jin Roh, M.D, Byung Gi Bae, M.D., Ju Hee Lee, M.D. Derpartment of Dermatology & Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea Psoriasis is a relatively common, chronic, inflammatory, multi-systemic disease, which predominantly manifested by skin lesions. The majority of psoriasis patients show mild to moderate severity and can be treated only with topical therapy or combination with topical therapy and systemic therapy. Therefore, topical therapy is important in the treatment of psoriasis because it can be used as initial monotherapy or adjunctive therapy with systemic drugs, phototherapy, or biologic therapy. Classical topical drugs include dithranol, tar, glucocorticosteroids, vitamine A derivatives and vitamine D derivatives. Topical corticosteroids are most commonly used drugs showing rapid response and excellent efficacy. For the purpose of improving quality of life and compliance to the topical steroid treatments, advanced formulations, such as spray or foam, have been developed. To solve side effects of vitamin D derivatives, such as skin irritation or abnormal calcium metabolism, new vitamin D derivatives have been developed. In addition, two-compound products containing calcipotriol and betamethasone dipropionate are being used as complementary drugs. These changes of classical topical drugs will be discussed in this review. Until now, topical agents are not sufficient to full control of psoriasis and showed side effects or limitations. There are many demand for the new paradigm topical agents with low side effects and high efficacy. New potential agents in the topical therapy of psoriasis are under the developmental phase or under the phase of clinical study. In the last few years, according to a novel understanding of the disease pathogenesis of psoriasis, there has been an increased interest in the research of new agents for 교신저자 : 이주희 서울시서대문구성산로 250 연세대학교의과대학피부과학교실 Tel: 02) Fax: 02) juhee@yuhs.ac the treatment of psoriasis. Antisense oligonucleotides, indigo naturalis, selective glucocorticoid receptor agonist, vitamin D receptor ligand, retinoic acid metabolism blocking agents (RAMBAs), agents inhibiting proinflammatory cytokines, topical methotrexate (MTX), janus kinase 3 (JAK3) inhibitor, and phosphodiesterase (PDE) inhibitors are emerged as new topical therapy Key Words: Psoriasis, Topical therapy 약 가 건선은비교적흔한만성염증성질환으로건선환자의 70% 가건선지수 (PASI) 가 10미만이거나침범된범위 10% 미만인경증혹은증등도건선이다. 대부분의경 증에서중등도의건선은국소치료제단독또는전신요법 과의혼합요법으로호전을기대할수있어건선치료에 있어서의국소제제의역할이매우중요하다. 또한건선 은전신적인치료를요하는경우에도완전관해가되는 경우가드물어, 국소치료제를관해를유지하는데사용하 기때문에최대한부작용이적으면서치료효과가높은 국소도포제의개발이필요하다. 따라서고전적인국소치 료제가가지는부작용과효과를개선시키기위한노력이 이루어지고있다. 지금까지사용되던고전적인건선의국 소치료제로는 dithranol, tar, 스테로이드제제, vitamine A 유도체, vitamine D 유도체등이있는데이들의효과 의한계성및부작용이부각됨에따라최근에는 spray, foam 등의다양한형태의제제가개발되어연구중이며, calcipotriol 과 betamethasone dipropionate 의혼합제 제가개발되어스테로이드와 vitamine D 유도체의장단 점을보완할수있게되었다. 또한, 최근에는기존고전적인국소제제를대체하거나 보완하기위한제제들이외에도건선의병인을차단하는 새로운기전의국소제제들과도포가능한생물학적제 제들에대한연구가활발히이루어지고있어, 최근연구 되고있는새로운국소제제들에대해서살펴보겠다.

2 대한건선학회지 Vol. 6, No. 1, 2009 고전적인국소치료제제의다양화 1. 국소스테로이드 (Topical corticosteroids) 스테로이드는효과가뛰어나며그효과가빠르게나타 난다는이점이있어현재까지도가장많이사용되는국 소치료제이다. 최근에는 clobetasol propionate 의 spray 형태 (Clobex spray) 와 foam 형태 (Olux foam) 가개 발되었다. 두가지형태모두사용감을향상시킴으로써 치료의순응도를높일수있으면서도효과는이전스테 로이드제제와차이가없어보다유용하게사용될수있 을것으로기대된다. 1-4 Spray 제제는 4주동안도포하였 을때 2주동안도포한것에비해부작용은차이가없으 면서효과는우수하였다. 4 또한이두가지제제를비교한 연구도있었는데중등도혹은중증의판상건선환자 77명 을대상으로 spray 와 foam 형태두가지제제로치료하였 을때효과와환자의만족도두가지측면모두에서 spray 제제가 foam 제제보다우수하였다 비타민 D 유도체 (Vitamin D derivatives) 새로운비타민 D 유도체로 becocalcidiol (2-methylene- 19-nor-0(S)-1a-hydroxy-bishomopregnacalciferol) 이 있다. 전임상연구 (preclinical trial) 에서이전비타민 D 유도체를고용량도포시생길수있는전신적부작용인 고칼슘혈증을일으키지않는것으로보고되었고, 6 beco- calcidiol을 5-25 μg/g 용량으로사용할경우에용량에 비례하여효과가나타나는것으로보였다. Helfrich 등 은판상건선환자 무작위통제연구에서 185명을대상으로한다기관이중맹검 becocalcidiol 을고용량 (75 μg/g) 으로 8주간도포하여 26% 환자에서완전관해가유도되 었음을보고하였다. 자극증상이부작용으로나타났지만 calcipotriol 을도포하였을경우보다낮은빈도이기때문 에효과와안전성면모두에서이전비타민 D 합성제보 다우수하다고보고하였다. 3. Calcipotriol 과 betamethasone dipropionate 합성제제 Calcipotriol 과 betamethasone dipropionate 은각각 안정도가높으며활성도가큰 ph가달라두제제를합성하 는데어려움이있었으나특수한제조기술을통해연고형 태로상품화 (Daivobet /Dovobet ) 되었다. Calcipotriol 은 1 g당 50 μg, betamethasone dipropionate 는 1 g당 0.5 mg 이포함되어있다. 현재까지보고된이중맹검무 작위통제연구를분석해보았을때 7개의임상연구에서 7 약 6,000명이상의환자를대상으로한결과 4주동안치 료하였을때건선지수 (PASI) 가 65-74% 정도감소하였 다 치료제를하루에 1번도포한군과 2번도포한군을 비교하였을때치료효과는치료전건선지수 (PASI) 정 도나환자나이와무관하였으며, 15 하루에 2번도포하는 것이 1번도포하는것보다더효과적이지않기때문에 1번 바르는것이권장된다. Calcipotriol 과 betamethasone dipropionate 의혼합제제는 calcipotriol 혹은 betamethasone dipropionate 를각각단독으로사용하였을때 보다좋은치료효과를보였으며, 1주일이내에치료효 과가빠르게나타나치료에대한순응도도높았다. 16 치료 효과는 5주째에최고로나타나며 8주까지는매일바르는 것이좋은것으로보고되고있다. 17,18 부작용으로는합성제제를하루 1번 4주동안도포하였 을때병변부위에서는 3%, 병변주변부위에서는 11% 의빈도로자극증상과가려움증이나타나는것으로보 고되었다. 그러나 8주동안지속적으로도포하였을경우 에부작용의빈도가더증가하지는않았다. 17 전신적인부 작용은위약군과비교하였을때차이가없었으며혈중 칼슘농도의증가도관찰되지않았다. 후향적으로 52주 동안도포한뒤부작용을본연구에서는 4.8% 환자에서 스테로이드성분으로인한부작용으로피부위축 (1.9%), 모낭염 (1.2%) 이가장많이나타났다. 이러한부작용은 calcipotriol 만을단독으로도포한군이나 calcipotriol 과 betamethasone dipropionate 합성제제를 4주씩번갈아 바른군과차이가없었다. 19 근래에들어서는두피건선의치료를위하여 calcipotriol 과 betamethasone dipropionate 혼합제제가겔형태로 상품화 (Xamiol ) 되었다. 현재까지보고된임상연구에 따르면 6개의연구가약 4,500명을대상으로이루어졌으 며 Xamiol 을사용한군이 Betamethasone dipropio- nate, calcipotriol 연고, calcipotriol 용액으로단독치료 한것보다효과가더뛰어났다 혈중칼슘농도의변 화, 피부위축, 팽창선조등의부작용은보고되지않았다. 52주동안장기간 Xamiol 을도포한뒤 calcipotriol을 단독도포한군과비교하였을때오히려작열감, 가려움증, 홍반, 자극증상등의부작용이적은빈도로나타났다. 24 새로운국소치료제제의개발 1. Indigo naturalis Indigo naturalis 는 Baphicacanthus cusia 의뿌리와잎에

3 노효진등 : 건선국소치료의최신지견 서추출한물질이다. 중국에서는전통적으로여러염증성 질환과피부염의치료로흔하게쓰여왔으며최근에는약 물학적으로 indigo naturalis 와활성성분인 indirubin 이 항바이러스, 항균, 항암작용이있다고밝혀졌다 Lin 등 29,30 은판상건선환자 14명을대상으로연고형태의 indigo naturalis 를국소도포하였을때임상적인호전을 보고하였으며 구를통해 42명을대상으로한시험자맹검통제연 12 주간도포한결과건선병변의인설, 홍반, 경화가의미있게감소하고 (p < 0.001), 42명중 31명에 서(74%) 도포한부위의건선병변이완전또는대부분소 실되었다고보고하였다. 치료중에생긴부작용으로는적 은수의환자에서가려움증이유발되었으나수일내로호 전되었으며이외의다른부작용은보고되지않았다. 2. Antisense oligonucleotides Antisense oligonucleotides 는 건선에서발현이증가 되어있는단백질들의발현을감소시켜병변을호전시킬 수있다. 특히 TNF- α에작용하는 phosphorothioate anti- sense oligonucleotide 가유용하며주로정맥혹은경구 투여로임상연구가진행되고있지만 7,701 달톤에달하 는큰분자량때문에국소도포를통해정상피부를통과 하기에는문제가있다 선택적스테로이드수용체작용제 (Selective glucocorticoid receptor agonist) 스테로이드는스테로이드수용체를통해서작용을나 타내게되는데, 활성화된스테로이드수용체는구조변 화를일으켜핵내로이동한후유전자의발현을조절하 게된다. Reichardt 등 32 은쥐에서스테로이드수용체에 점돌연변이 (point mutation) 가있을때이합체화 (dimerization) 가되지않아스테로이드수용체의유전 자활성기능이없어지는것을관찰하였으며이돌연변 이쥐에스테로이드를적용할경우부작용은나타나지 않으면서항염증작용은동등하게나타나는것을확인하 였다. 이후선택적스테로이드수용체작용제의개념이 등장하였고현재까지 AL-438, LGD-5552, ZK 등 의제제가개발되어실험적으로는효과적이라고보고되 었지만아직까지임상연구는충분하지않다 또한 Mark 등 36 은 NO-donating prednisolone 유도체 (prednisolone 21-[4 -(nitrooxymethyl)benzoate] 를통 해서스테로이드수용체를 nitration 시켜항염증작용을 증강시킬수있음을실험적으로증명하였다. 4. 레티노산대사방해제 (Retinoic acid metabolism blocking agents (RAMBAs)) 최근에들어서는비타민 A의체내대사물인 All-trans retinioic acid (ATRA) 의분해를막는기전으로기존비 타민 A 치료제의부작용을없애고동등한효과를얻을 수있는제제들이개발되어임상시험중에있다. ATRA 의분해는 microsomal cytochrome P450 (CYP) 의존효 소에의해서조절되며효소에는 CYP26A1, CYP26B1 그 리고 CYP26C1 가있다. 이러한효소의활성을막으면체내 ATRA 의농도를증가시켜치료효과를얻게된다. 이러한 방해물질을 retinoic acid metabolism blocking agents (RAMBAs) 라한다. 건선과어린선 (ichthyosis) 에서효과 가입증된최초의 RAMBA 는 liarozole 이다. 37,38 하지만 liarozole 은 ATRA 관련효소에대한특이성이떨어지며 다른부신호르몬의생합성도막을것으로생각된다. Talarozole 은 CYP26 에더높은특이도를가지는 RAMBA 로건선에서는국소도포제제로 0.07% 제제와 0.35% 제 제의임상 1 상연구가완료되었다. 5. 새로운비타민 D 수용체리간드 (Ligand) 비타민 D 수용체리간드인 calcipotriol, tacalcitol, calcitriol 은경도혹은중등도의건선에있어효과적으로 사용될수있지만드물게장세포 (intestinal cell) 에작용 하여고칼슘혈증, 고칼슘뇨증을일으킬수있는문제가 있었다. 이에좀더특정조직에특이도를가지는제제의 개발이이루어지고있다. Yanfei 등 39 은이전의비타민 D 수용체리간드의기본골격을변화시킨제제 (nonsecosteroidal VDR ligands; LY , LY ) 를개발 하여각질형성세포와골모세포, 말초혈액단핵구에선택 적으로작용하면서장세포에는영향을주지않음을실험 적으로증명하였다. 동물실험에서는전신치료를하였을 경우에순수비타민 D 수용체리간드 (1,25-dihydroxyvitamin D3 [1,25-(OH) 2D 3 ] 보다약 270배의효과가있음 을보고하였다. 6. 전염증사이토카인을억제하는생물학적제제 p38 MAP kinase (MAPK) 는여러세포에서발현되며 세포외부의스트레스혹은자극, 쇼크등에반응하여여 러사이토카인 (IL-1, TNF, IL-6), nitric oxide, prostaglandin/prostacyclin, cyclooxygenase 2 를분비하고 matrix metalloproteinase 를분비하여염증반응을일으 키는데중요한역할을한다. MAPK를억제할경우염증

4 대한건선학회지 Vol. 6, No. 1, 2009 성질환을치료할수있을것으로생각되어왔다. BIRB796 은류마티스관절염, 크론병, 건선등에서임상 연구가진행되었다. 판상건선환자에서경구제제로 4주 동안치료한결과건선지수 (PASI) 가호전되지는않았지 만조직검사상에서는호전을보였다. 40 p38 α-, β-, γ-isotype을억제할수있는제제로 VX-745 는류마티스관절염에서경구제제로임상 2상연구를진 행했었지만신경학적문제가동물실험에서발견되어중 단되었다. 41 근래에는 p38 α-isotype 에특이도가높은제 제인 VX-702 가개발되어임상연구중에있다 국소 Methotrexate (MTX) Methotrexate (MTX) 는 folic acid 의길항제 (antagonist) 로서 dihydrofolate reductase의방해제로작용하여건 선에서는상피세포의분열을막아서치료효과를나타낸 다. 그러나전신적인치료를지속할경우에는적혈구감 소, 백혈구감소, 혈소판감소, 간독성, 설사, 복부자극감 등의부작용이있을수있어사용이제한된다. 따라서 MTX 를국소도포제제로사용하여전신적인부작용을 줄이며치료효과를얻고자하는노력이이루어져왔다. Eskicirak 등 43 은 40명의판상건선환자를대상으로 1% MTX 겔제제를 8주동안도포한뒤위약을도포한 군과의임상적인호전을비교하였다. 전반적인임상호전 은 1% MTX 겔을도포한군의 97% 에서관찰되었으며 (p < 0.01), 건선병변의조직학적인소견도호전되었다 (p < 0.01). 특이부작용은보고되지않았다. MTX 도포제제의피부투과율을증가시키기위한여 러노력도이루어져왔다. 대표적으로세포막과유사한 막인인지질 (phospholipid) 으로주성분으로해서만들 고안쪽에는약물을포함시키는리포솜 (liposome) 과비 이온성계면활성제로막을형성하는니오솜 (niosome) 을이용한연구가진행되었다. 이러한방법이단순히 MTX 겔만을도포하는군에비해치료효과를높일수있 음을보고하였다. 44,45 8. Janus kinase 3 (JAK3) 억제제 Janus kinase 3(JAK3) 는면역세포에만국한되어표현 되는것으로알려져있으며 JAK/STAT 신호전달경로에 서감마고리 (gamma-chain) 를가진사이토카인수용체 에만붙는것으로알려져있다. 따라서 JAK3를선택적으 로억제할경우이전면역억제제에비해부작용은적으 면서치료효과는높일수있을것으로기대됐다. 최근 들어 JAK3를선택적으로억제하는약제인 CP-690, 550 이개발되어임상시험중에있다. 류마티스관절염에서는 임상 2상과 3상시험이진행중이며건선에서는국소도 포제제로임상 2 상시험중에있다 Phophodiesterase (PDE) 억제제 PDE는 cyclic nucleotides (cgmp, camp) 를분해하는 데중요한역할을하는효소로지금까지 지 11 개의그룹이알려져있다. PDE는 1-11까 PDE4는 cyclic AMP (camp) 분해효소로서호산구, 호중구, 대식세포, T 세포등의염증세포와각질세포, 섬 유모세포에도존재한다. PDE4를억제하면사이토카인의 생성및분비억제, IgE 의생성억제, 히스타민의생성 억제등을통해함염증작용이있을것으로생각된다. 현 재까지개발된 PDE4 억제제로는 CC-10004, AWD , Roflumilast, AN2728 이있다. 특히 AN2728 (5-(4- Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxab orole) 은말초혈액단핵구세포에서의 TNF- α, IFN-γ의 분비를억제하는것으로알려져있으며현재국소도포용 제제로개발되어건선환자를대상으로임상 에있다. 47 2상연구중 PDE7은 camp에특이도를가지는효소이며 PDE7A 와 PDE7B 가있다. 이중 PDE7A 는비장, 림프절, 백혈구 에표현된다. Smith 등 48 은실험을통해 PDE7 억제제가 사람의단핵구, T 세포, 폐의대식세포에서 TNF-α의분비 를억제함을보고하였다. 최근 Kumiko 등 49 은 PDE7A 억제제인 ASB16165 (1-Cyclohexyl-N-[6-(4-hydroxy-1- piperidinyl)-3-pyridinyl]-3-methyl-1h-thieno[2,3-c]py razole-5-carboxamide monohydrate) 를개발하여이제 제를국소도포하였을경우 12-O-tetradecanoylphorbol- 13-acetate (TPA) 에의해유발된쥐의귀염증이호전됨 을확인하였다. 이를통해 PDE7A 억제제가건선의국소 치료에쓰일수있는가능성을확인하였다. 결 이제국소제제는단순히건선의일차치료제의단계를 뛰어넘어, 기존치료제의부작용을보완하고보다근본적인 건선발생과관련된원인을차단하기위한치료에도전하고 있다. 최근밝혀지는건선의병태생리학적기전에따라새 로운파라다임에맞는최대한효과적이면서부작용을최소 화한국소제제들이향후개발되어야할것으로사료된다. 론

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Calcipotriene/betamethasone dipropionate gel compared to gel vehicle in treatment scalp psoriasis in Hispanic/Latino and black/african American patients.

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대한건선학회지 Vol. 6, No. 1, 2009 연구대상 및 방법 결 과 1. 연구대상 2007년 11월부터 2008년 8월까지 본원 피부과 외래를 방문한 건선 환자 중 18세 이상이면서 Body Surface Area (BSA) 10% 이하, Psoriasis Ar

대한건선학회지 Vol. 6, No. 1, 2009 연구대상 및 방법 결 과 1. 연구대상 2007년 11월부터 2008년 8월까지 본원 피부과 외래를 방문한 건선 환자 중 18세 이상이면서 Body Surface Area (BSA) 10% 이하, Psoriasis Ar 대 한 건 선 학 회 지 제 6 권, 제 1 호 Journal of the Korean Society for Psoriasis Vol. 6, No. 1, 23-27, 2009 경도 혹은 중등도 건선치료에서 Calcipotriol/Betamethasone Dipropionate 혼합 제제와 Calcipotriol/Methylprednisolone Aceponate