02-김남희

Transcription

1 대한임상신경생리학회지 8(1):6~15, 2006 ISSN 말초신경병증에대한정맥내면역글로불린요법 동국대학교의과대학일산병원신경과학교실, 서울대학교의과대학분당서울대병원신경과학교실 김남희 박경석 Intravenous Immunoglobulin Therapy in Peripheral Neuropathy Nam Hee Kim, M.D., Kyung Seok Park, M.D.* Department of Neurology, Dongguk University International Hospital, Goyang-si; Department of Neurology, Seoul National University College of Medicine*, Seoul, Korea Intravenous immunoglobulin (IVIg) is the treatment of choice for many autoimmune neuropathic disorders such as Guillain-Barre syndrome (GBS), chronic inflammatory Demyelinating neuropathy (CIDP), and multifocal motor neuropathy (MMN). IVIg is preferred because the adverse reactions are milder and fewer than the other immune-modulating methods such as steroid, other immunosuppressant such as azathioprine, and plasmapheresis. IVIg also has been used in other autoimmune neuromuscular disorders (inflammatory myopathy, myasthenia gravis, and Lambert-Eaton myasthenic syndrome) and has been known as safe and efficient agent in these disorders. Since IVIg would get more indications and be used more commonly, clinicians need to know the detailed mechanism of action, side effects, and practical points of IVIg. Key Words: Intravenous Immunoglobulin (IVIg), Neuropathy, Autoimmune diseases, Guillain-Barre syndrome, Chronic inflammatory demyelinating neuropathy, Multifocal motor neuropathy 서 론 고용량의정맥내면역글로블린요법 (Intravenous immunoglobulin; IVIg) 은 Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating neuropathy (CIDP), multifocal motor neuropathy (MMN) 등과같은자가면역성신경병증 (autoimmune neuropathy) 에있어효과적인치료법이다. 스테로이드나혈장치환술, 기타면역억제제등도이러한질환들에서사용되기도하나그부작용이심하며효과가일정치않아, 쉽고안전하며효과적인 IVIg 가더선호되고있다. 1 지난 20 여년간고용량 IVIg 는이러한자가면역성신경 Address for correspondence Kyung Seok Park, M.D. Department of Neurology, College of Medicine, Bundang Seoul National University Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, , Korea Tel: Fax: pks1126@chol.com 병증들외에도염증성근질환, 람버트-이튼근무력증후군 (Lambert-Eaton myasthenic syndrome: LEMS), 중증근무력증 (Myasthenia gravis: MG) 등여러자가면역성신경근질환들에서효과적이며안전한치료법임이밝혀져왔으며, 현재도수많은연구들에서이의유효성을입증되고있다. 2 본고에서현재까지알려진 IVIg의약동학적특성, 작용기전및자가면역성신경병증들에서의적용, 부작용등에관하여알아보고자한다. 1. IVIg 의생산및약동학 IVIg는 3천에서만명의공여자로부터얻은혈장에 cold ethanol fractionation (Cohn s process) 방법을처리하여생산된다. 3 이후효소처리를통하여정제되고 fractionation과크로마토그래피를거치며, C형간염등의바이러스를불활성화시키는세정처리를거친다. 4 이렇게정제된면역글로블린을 glucose, maltose, glycine, sucrose, mannitol, 또는 albumin 등으로안정화시킨다. 1 시판되고있는 IVIg는 IgG를 95% 이상, IgA를 2.5%, IgM를극소량포함한다. 3 IgG의구성은 IgG 1 이 55~70%, IgG 2 가 0~6%, IgG4가 0.7~2.6% 를차지하며 6 Copyright 2006 by the Korean Society for Clinical Neurophysiology

2 말초신경병증에대한정맥내면역글로불린요법 이는공여자구성에따라달라진다. 1 모든 IVIg 제품들이농도, 안정화제제, IgA 구성비, IgG 세부구성비, 산도등이동일하지는않지만, 그생물학적작용이생산되는제품마다다르다고아직입증된바도없다. 1 약동학적으로살펴보면, 2 g/kg IVIg를정주하면혈청중의 IgG가 5배증가되나, 72시간에는 50% 정도감소되며, 21~28일후에는정주전의농도와같아진다. 5 인체의고유한면역글로블린의반감기와같이 IVIg 제제의반감기는 18~32일이므로, 혈청에서초기 72시간에 50% 정도감소되는것은혈관외로의급속한재배치에의한것이다. 1 혈청 IgG가최고치를유지하는정주후초기 48시간동안, 뇌척수액에서는 IgG의농도가 2배로증가되며 1주일후에는정상치로감소된다. 6 정주된 IVIg이 blood- CSF barrier가적은신경종판부나신경근부위로더쉽게들어가서작용할것으로추측되지만, IVIg가면역체계에전반적으로작용하는효과와더불어이부위들에서국소적으로더작용을나타내는지는아직밝혀져있지않다 IVIg 의작용기전 수많은연구들을통하여 IVIg 의다양한작용들이밝혀져있다. 각각의신경근질환에대해서는각질환의면역 병리학적원인에따라주로작용하는기전들이설명되고있다 (Table 1). 1 이기전들가운데일부는 in vivo, in vitro 연구를통하여잘밝혀져있지만다른일부는 IVIg 에반응하는자가면역질환들의기전에대한정보를통하여추론되기도하였으며아직많은부분이가설이므로추후여러연구를통하여밝혀져야한다. 1) 자가항체에대한작용 (Effect on autoantibodies) IVIg는여러공여자로부터생산되어다양한 idiotypic, anti-idiotypic 특이성을가진항체를포함하며, IgG분자들이 dimer로존재하는비율이 40% 정도된다. 8 Fab는자가항체의항원결합부위이다 (Fig. 2). 2 정주된 IVIg는세가지기전을통하여작용한다.1 첫째는 anti-idiotypic 항체로서중화작용을한다. IVIg의 Fab부위가병을일으키는자가항체 (autoantibodies; anti-acetylcholine receptor (AchR), anti-gm1, anti-thyroglobulin 등 9-12 ) 에결합하여결국자가항체의자가항원 (autoantigen) 과의결합을방지하는작용을한다 (Fig. 3A). GBS 환자들에서얻은다양한 IgG glycolipid 항체의신경근조직에대한 blocking effect 가 IVIg에의해중화됨이관찰된바있다. 13 둘째는 IVIg의 anti-idiotypic 항체가 B세 Table 1. Proposed mechanisms of action of IVIg and their relevance in the respective autoimmune neuromuscular disease actions of IVIG Neuromuscular 1. Effect on autoantibodies by (a) Autoimmune demyelinating (a) neutralizing pathogenic autoantibodies neuropathies (CIDP, GBS, MMN) (b) affecting antibody production (b) MG. (C) LEMS (d) SPS (c) accelerating catabolism of IgG antibodies by saturating FcRn transport receptor 2. Inhibition of complement binding and prevention (a) GBS. (b) CIDP. (c) DM. (d) MG of membranolytic attact complex formation 3. Modulation or blockade of Fe receptors (a) GBS. (b) CIDP. on macrophage (c) Inflammatory myopathies 4. Suppression of pathogenic cytokines and other (a) Demyelinating neuropathies immunoregulatory molecule (b) MG. (c) Inflammatory myopathies 5. Modulation of T-eell Function and antigen (a) GBS. (b) CIDP. recognition (c) Inflammatory myopathies 6. possible effect on remyelination (a) GBS. (b) CIDP. 7. Effect on superantigen (a) GBS. (b) CIDP. (c) MG 8. Interaction With antigen-presenting cells (a) Demyelinating neuropathies (b) Inflammatory myopathies (c) MG J Korean Society for Clinical Neurophysiology / Volume 8 / June,

3 김남희 박경석 포에대하여억제신호를주어항체생성에영향을준다. 14 IVIg 에는 CD5 에대한항체가있어자가항체생성에관여하는 CD20+B 세포에영향을주어항체생성을억제시킨다 (Fig. 3B). 15 셋째로 IVIg 는 endocytic vesicle 에있는 protective transport receptor (FcRn) 를포화시킨다. 따라서 IVIg 에서기인한많은수의 IgG 가분해되지않고다시순환되어나감에따라상대적으로병을일으키는자가항체가 protective transport receptor 의도움을받지못하게되어분해되어버리는식이다. 따라서 IVIg 의이러한작용으로병을일으키는자가항체 (IgG) 의많은수가분해되어버려서전체적으로병을일으키는자가항체가줄어들게된다. 16 이와같은자가항체에대한 IVIg 의작용은 GBS, CIDP, MG, LEMS 등과같은자가항체매개성의자가면역질환에서의 IVIg 작용기전과연관된다. 1 2) 보체결합억제와세포막공격체형성방지작용 (Inhibition of complement binding and prevention of membranolytic attack complex formation) IVIg의보체결합에대한작용은잘알려져있다. IVIg 는보체 C3와 C4가혈관내피세포로흡수되는것을억제시킴으로써보체의존성 Forssman shock으로기니아 피그 (guinea pig) 가죽는것을방지한다. 17 피부근염 (der matomyositis: DM) 에서의보체의존성미세혈관병증은 C3의활성화와 endomysial capillary에세포막공격체 (MAC) 의침착을통해발생하는데, IVIg가이러한보체의흡수를억제하며 MAC가 endomysial capillary에침착되는것을방지한다. 즉정주된 IgG가 C3와결합함에따라 C5 convertase assembly의형성에관여할수있는 C3가감소되고결국 MAC의침작을방지하게되며, 이는근조직생검상에서도확인되었다. (Fig. 4). 18 이러한 IVIg의보체에대한작용기전은 GBS, CIDP, MG 등보체활성화와관련된다른자가면역성질환들에서도아직객관적입증은되지않았으나관련될것으로생각된다. 19 3) 대식세포에대한조절 (Modulation or blockade of Fc receptors on macrophage) 각각의면역글로블린에대한특정 Fc수용체가대식세포에존재하는데, IVIg는이러한대식세포의 Fc수용체를포화시키며수용체의친화도를떨어뜨려서, Fc수용체의작용을막아포식작용 (phagocytosis) 을억제시킨다. 20,22 GBS와 CIDP에서 IVIg는대식세포의 Fc수용체의기능을막음으로써항원을나타낸표적세포의대식세포에의한포식작용을억제하여대식세포에의한탈수초화를방지한다. 22 Figure 1. Main immunologic networks involved in autoimmune neurological disorders. VIg effects include (1) interference with costimulatory molecules; (2) provision of anti-idiotypic antibodies or suppression of antibody production; (3) interference with the activation of complement and interception of MAC formation; (4) modulation of the expression and function of Fc receptors on macrophages; (5) suppression of cytokines, (6) chemokines, and (7) adhesion molecules; and alterations of the activation, differentiation, and effector functions of T-cells. (Modified from Dalakas MC, 2004). 8 J Korean Society for Clinical Neurophysiology / Volume 8 / June, 2006

4 말초신경병증에대한정맥내면역글로불린요법 4) 사이토카인등면역조절물질의억제 (Suppression of pathogenic cytokines and other immunoregulatory molecules) In vitro, in vivo 연구를통하여 IVIg가용량의존적으로하게 IL-1, TNF-α, IL-1β, TGF-β, TGF-βmRNA, MHC-I, ICAM-I, LFA-1과같은사이토카인이나 adhesion molecule 등의감소를일으킨다고밝혀져있다. 23,26 GBS에서 IVIg 정주 1주후에림프구에서 ICAM- I의감소가관찰되었다. 27 대개의자가면역성신경근질환들에서사이토카인이나 adhesion molecule의 up-regulation이존재하는바, IVIg에의한 down-regulation 의작용은이러한질환의조절에있어매우중요한기전중의하나이다. 28,29 5) T세포에대한조절 (Modulation of T-cell function and antigen recognition) IVIg는일시적인림프구감소를일으키기도하며, 30 T 세포의항원인식을간섭하는 CD4, CD8, HLA-I, HLA- II, TGF-β등을포함하고있다. 31 또한 HLA-I의 α 1 helix를인식하는항체들을포함하며, 이러한항체들은 HLA-I 항원들과결합하여 CD8-매개성세포독성 ( 염증성근염과같은 T세포매개성자가면역성질환에서의주요기전임 ) 을억제한다. 32 6) 이외의작용들 (1) 수초재생효과 (Possible effect on remyelination) IVIg 는실험적인 allergic neuritis 모델에서수초 (myelin sheath) 에직접적으로작용하여수초재생의효과가있다고알려져있으나, 33 이러한작용이탈수초성신경병증의회복에실제기여하고있는지는아직더연구가필요하다. 34 (2) 초항원에대한작용 (Effect on superantigen) 초항원은 Vβchain을나타내는비감작 T세포를자극하여사이토카인을분비시켜자가면역성신경근질환을일으키거나질환의재발을유도한다. 35 IVIg에는이러한초항원과 T세포수용체의 V β3, V β8, V β17 에대한항체를포함하므로, 36 초항원의자극에의한세포독성 T세포의증가를억제시킬수있다. MG, CIDP, GBS 등의질환치료에서이에의한기전이관련된다. (3) 항원제시세포와의상호작용 (Interaction with antigen-presenting cells) IVIg는 dendritic 세포의분화와성숙을억제하며사이토카인분비와항원제시와연관된자극물질들을또한억 37, 38 제시킨다. 이러한기전은 CIDP 등의자가면역성질환대부분의치료에서적용된다. 3. 자가면역성말초신경질환에대한 IVIg 치료의실제 1) Guillain-Barre syndrome (GBS) 급성탈수초성신경병증으로발병 2 주안에증상이최고조에이르며, 심한사지마비, 호흡마비등을일으키기도한다. 표적항원이무엇인지는아직밝혀져있지않으나체액성과세포성면역기전이모두관련되며, 보체의활성화와수초에대한 MAC 의침착, antiganglioside 또 Figure 2. Schematic drawing of immunoglobulin molecule and formation of dimers in immune globulin. (Right) Immune globulin in a purified preparation derived from multiple donors (IVIg) contain 40% dimers, as the result of double-arm and single-arm binding, and 60% monomers. (Modified from Dalakas MC, 1999). J Korean Society for Clinical Neurophysiology / Volume 8 / June,

5 김남희 박경석 는 glycolipid 항체의존재, T세포활성화와사이토카인의증가, 감작된대식세포의수초침범등이관찰된다. 39 과거에는심한 GBS의초기에혈장치환술이사용되어회복기간을단축하였다. 최근연구에의하면 IVIg가혈장치환술과동등하거나더나은효과를나타낸다. 41 또한 IVIg와혈장치환술의병합요법이 IVIg단독요법과크게효과면에서차이나지않으며 IVIg와 IV methylprednisone의병합시에도단독요법과큰효과의차이는없다. 42 Miller-Fisher variant의경우도 IVIg가효과가있으나이에대한체계적연구는아직없다. 43 (1) 용량최적의용량을알아내기위해 3일간총 1.2 g/kg를준경우와 6일간 2.4 g/kg를준경우를비교한결과, 6일치료군이근력을회복해서걷는데까지걸리는시간이더짧았고, 1년째에근력이완전히회복된비율이더높았다. 44 이를토대로적어도 2 g/kg 이상의용량을일반적으 로사용한다. (2) 초기재발일부환자들에서혈장치환술또는 IVIg 에대해효과를보이나금방재발하기도하는데, 이러한재발율은혈장치환술과차이는없다. 45 대개치료에대한반응이빠를수록재발율은떨어진다. 45 (3) 2 차치료 IVIg 정주후 3 주가되어도그효과가미미한경우 2 차치료를고려하게되는데, 아직이를뒷받침하는체계적인연구결과는없으나, 일부환자들에서 1 차치료에 3~4 주지나도반응이별로없을경우 2 차치료를하면효과가있다고보고된바있다. 46 (4) GM1 항체 Axonal form GBS 의경우 Camphylobactor jejuni 나 GM1 항체와관련성이높다. 이러한환자군에서는혈장치환술보다 IVIg 에오히려더반응이좋기도하며, Table 2. Adverse reactions of IVIg Side effects of IVIg Generalized and systemic reactions Neurological complications Hypersensitivity Renal complications Cardio-vascular reactions Miscellaneous effects Headache Myalgia Fever/chills Low back pain/ chset pain Nausea/vomiting Elevated liver enzymes Transient neutropenia Hyperglycemia Aseptic meningitis Migraine Stroke Reversible encephalopathy with intracranial vasospasm Anaphylactic reactions (esp. with IgA-deficiency) Hemolytic anemia Immune complex mediated arthritis Hypersensitivity myocarditis Acute renal failure Hypertension Cardiac failure Tachycardia Thromboembolic events Uveitis Alopecia Hypothermia 10 J Korean Society for Clinical Neurophysiology / Volume 8 / June, 2006

6 말초신경병증에대한정맥내면역글로불린요법 GM1항체를가진경우더회복이빠르고, 47 axonal degeneration의정도가심하고특히근위부에있거나, Camphylobactor jejuni 감염과관련된경우는회복이더디다고알려져있다. 48 그러나또다른연구에서는혈장치환술과의치료효과의차이는없다고보고되어 42 아직은논란의여지가있다. 2) Chronic inflammatory demyelinating polyneuopathy (CIDP) 수주또는수개월에걸쳐서서히발병하며근위약, 건반사소실, 감각저하등이특징적이다. 면역병리는 GBS와유사하다. Molecular mimicry, antiglycolipid 항체, T 세포감작, 활성화대식세포에의한수초손상, 보체활성화등이주요한면역병리소견이다. 39 예전부터 steroid가 first choice로간주되어 steroid-responsive neuropathy 라는별칭이있기도한데최근의연구결과를통해보면 IVIg나혈장치환술도 steroid와비슷하거나오히려약간더나은치료효과를보인다. 49 이외에 diseaseassociated variants of CIDP의경우, 예를들어 DM- CIDP 등에서도 IVIg의효과가있는것으로간주되나아직구체적인증거는없는실정이다. 1 (1) 유지요법 IVIg 투여시평균적으로약 9일후에호전을나타내며 4~6주후에최대의호전을나타낸다. 1 호전을유지하기위해서는대개 2 g/kg의용량을 4~6주마다반복하여치료해야한다. 1 1 g/kg 정도의저용량을유지해도된다는보고가있으나, 50 아직은이에대한추가적연구가더필요하다. 초기치료에호전을보인경우에도추후치료에서같 은호전반응이유지되지않기도한다. 일반적으로 axonal change까지나타난경우는치료에어려움이있다. (2) 치료법의선택및예후인자 Steroid, IVIg, 혈장치환술모두치료효과가비슷하다. 치료의선택에있어비용, 장기간사용시의부작용, 환자의나이, 혈관상태, 병의중증도, 동반된다른질환등을고려하여최근에는 IVIg가더선호되는경향이다. 1 물론아직도일부에서는 steroid를선호하기도한다. 환자에따라더잘반응하는치료법이다를수있는데아직그이유는밝혀져있지않아서, 복합요법이선호되기도한다. IVIg에대해치료효과를더뚜렷이나타내는요인을연구한결과, (a) 이환기간이 1년내인경우 (b) 근위약이치료직전까지계속진행한경우 (c) 팔이나다리의근위약이비슷한정도로나타나있는경우 (d) 팔의건반사가소실된경우 (e) 정중신경의운동신경전도속도가느려진경우 ( 즉진행하는, 전신적인, 최근의탈수초화를나타내는모든징후들 ) 등으로이러한 5가지의조건에모두부합한경우 IVIg에대한효과가 90% 라고한다. 51 또한급성악화를보이는경우 IVIg가더효과적이다 53. 비용적인측면을감안할때, steroid가약가는저렴하여단기간비용은적지만 2~3년간장기사용시합병증 ( 골다공증, 당뇨, 백내장, 고혈압, 비만 ) 에따른비용적인측면을고려하면 IVIg가좀더유리하다. 3) Multifocal motor neuropathy (MMN) 서서히진행하는근위약과근위축이주로상지원위부에있으며건반사의감소가있으나감각기능은정상으로나타난다. Conduction block 이특징적으로나타나며 A B Figure 3. Effect on autoantibodies. (A) Proposed effect of immune globulin on anti-idiotypic network. (Left) Idiotypes recognize autoantigen on the surface of cell; (Right) the variable region of the circulating idiotypes and prevents them from reacting with autoantigen. (B) Proposed scheme of binding of immune globulin to Fc receptors on B lymphocytes. The IgG in the immune globulin crosslinks with the Fc receptors on cell surface (1) and could exert a feedback inhibition on antibody production by B cells. The variable region of the IgG also interacts with surface antigens (2) or with antigenic determinants on the cell-surface immunoglobulin (3), causing negative signals on B cells and downregulation of antibody production. J Korean Society for Clinical Neurophysiology / Volume 8 / June,

7 김남희 박경석 GM1 ganglioside에대한항체가있는경우가많다. CIDP와는달리 steroid 나혈장치환술에는반응이없으나 IVIg에는뚜렷한치료효과를나타낸다. 52 증상의호전은 CIDP와유사하게 7~10일후에발생하며 4~6주간지속되고, 이때다시새로운 2 g/kg의 IVIg의정주가요구된다. Motor axon의소실이이미나타난만성 MMN의경우도 IVIg에대해어느정도증상의호전및전기생리학적소견의개선을보일수있다. IVIg 치료법은 MMN에서일차선택치료이다. 그러나이에호전되지않는일부의환자에서 cyclophosphamide 정주를함께시행하면효과를보이기도한다. 장기간유지요법을위해서는초기 0.4 g/kg으로 5일간정주후 1주마다한번씩 0.4 g/kg으로약 1년간유지하며이후정주빈도와용량을조절한다. 52 이렇게하면근력은대개 3주내에호전되나이후기간동안에약간근력이감소되기도한다. 전기생리학적으로도임상양상의변화에따라호전과악화를반영하며전도차단 (conduction block) 이없어지기도하는데, 52 이는 IVIg 유지요법이 MMN의치료에유용하며면역병리에도영향을주고있음을반영하는소견이다. 4) Paraproteinemic demyelinating polyneuropathy Figure 4. Effect of immune globulin on complement deposition. Activation of the complement pathway on the cell surface begins by binding of the C1q on the antigen-antibody complex, triggering the cascade of C3 activation. This leads to the activation of C3b fragments and the formation of MAC, which causes cell lysis. Immune globulin inhibits complement deposition (dotted arrows) by acting on the C3b fragments and preventing the incorporation of C3 molecules into the C5 convertase assembly. The formation of MAC is therefore inhibited and cell lysis is prevented. IgG 나 IgA monoclonal gammopathy 와연관된탈수초성신경병증은 CIDP 와유사한임상양상과치료에대한반응을나타낸다. 그러나 IgM monoclonal gammopathy 와연관된탈수초성신경병증 (IgM-DP) 의경우전자와는다른임상양상을보인다. 이러한환자중 50% 이상은 myelin-associated glycoprotein (MAG) 와 sphingoglycolipid 에대한항체를지니며임상적으로는 sensory ataxia 또는 sensorimotor neuropathy 를주로나타낸다. Anti-MAG 신경병증은치료에대한반응이좋지않지만, IVIg 에대한최근연구에서는통계적으로는유의하게반응하였다. 53 IgM 이높아져있는경우혈청의점도가상승하여 IVIg 정주시추가적으로점도상승을일으켜혈관폐색을일으킬수있으므로주의를요한다. 4. IVIg 치료법의유의점 대개 2 g/kg 를투여하며 5 일간에투여하는것이일반적이다. 그러나젊은연령에서신장이나심질환이없는경우는 2 일간에나눠투입하는것이선호되기도한다. 54 IVIg 가혈장외로빨리확산되어나가는것을감안하면고농도로단기간에투여하는것이더효과적일가능성이높다. 정주속도는 200 ml/hr 또는 0.08 ml/kg/min 을넘지않아야한다. 1 투여기간에관한연구들에서 2 g/kg 을분할하여투여하는것에비해한꺼번에단기간에투여하는경우사이토카인중화, Fc 수용체조절, C3 의억제등의측면에서더유리하다는결과가있다. 55 1) 부작용및위험인자 일반적으로 IVIg 치료법의부작용빈도는 10% 정도이다 (Table 2). 54,56 NSAID에잘반응하는경도의두통이가장흔한부작용이며, 오한, 근육통, 가슴통증등이정주 1 시간내에발생될수있으나 30분정도정주중단시대개사라지며, 이경우정주속도를더느리게하여야한다. 정주후에는피로감, 열감, 오심등의증세가올수있고 24시간정도지속되기도한다. 이러한부작용의원인은뚜렷하지않으나보체의활성화에따른반응일가능성이높다. 3,54 심장질환, 울혈성심부전시는정주속도를늦추도록한다. (1) Serum viscosity and thromboembolic events IVIg는혈액의점도를올리는데특히 hypercholesterolemia, cryoglobulinemia, hypergammaglobulinemia의경우점도는더올라갈수있다. 정상혈액점도는 1.2~1.8 cp정도이나 2.5 cp이상의점도가되면혈관폐색의위험이증가되어뇌경색, 심근경색, 폐색전등이발생한다. 57 최근의정맥혈전증이있었던경우나움직일수없는상태인경우혈관폐색의위험성을고려하여초음파로하지의혈전에대한확인이필요하며정주속도를아주늦추어야한다. 이러한경우저용량헤파린이나항혈소판제제를투여하여예방할지에대해서는아직결론이없다. 12 J Korean Society for Clinical Neurophysiology / Volume 8 / June, 2006

8 말초신경병증에대한정맥내면역글로불린요법 (2) Migraine headache IVIg는편두통을유발시킬수있으므로편두통병력이있는경우는 propranolol을전처치하여예방하기도한다. IVIg를편두통병력있는젊은여성에게투여시뇌졸중을일으킨보고도있다. (3) Aseptic meningitis 무균성수막염은정주속도나 IVIg제제의첨가성분등과는특별히연관이없으며, 강한진통제에잘반응하고대개는 24~48시간내에두통은가라앉는다. 5 특별한진단적인검사는필요치않다. (4) Skin reaction 정주후 2~5일후나타나며 30일정도지속되기도한다. 담마진, 라이켄양병변, 손바닥의소양감, 사지의점상출혈등이소수의환자에서나타난다. 54 (5) Severe anaphylactic reaction IgA가없거나감소된환자들에서발생한다. IgA 감소는비교적흔하여유병율은 1:1000 정도이나, IgA 감소환자모두에게서발생하는것은아니다. IVIg 가운데소량들어있는 IgA가순환 anti-iga 항체와반응하여 macromolecular complex를형성하여나타난다. IgA 감소환자중 29% 에서 anti-iga 항체가존재하며, 이들중일부에서만이러한부작용이나타난다. 58 (6) Renal tubular necrosis 급성신세뇨관괴사가드물게나타나며이는가역적이다. 이전에신장질환이있고탈수상태, 노인, 당뇨등을지닌환자에서나타날수있다. 혈청크레아티닌이정주후 1~10일사이에상승될수있으며정주를중단하면 2~60일후정상화된다. 59 이는 IVIg 제제중포함된고농도의 sucrose와관련있으며삼투압에의한세뇨관손상의결과이다. 59 따라서 IVIg를희석하거나정주속도를늦추거나삼투압낮은제제를사용하여세뇨관괴사의위험을줄이도록하며, 신질환이있는경우 IVIg를사용할때 creatinine과 BUN의변화를주의깊게관찰해야한다. 59 (7) Spurious results on serological tests IVIg 투여후 ESR이 6배까지상승하기도하는데, 2~3 주지속되기도한다. 30 또한저나트륨혈증이관찰되기도한다. 30 결 론 IVIg 는면역이상에의한각종신경계질환의치료에이용되고있다. 현재잘고안된임상시험결과를바탕으로 GBS, MMN, CIDP 등의말초신경병증에서는 IVIg 가일차선택치료로이용되고있다. 그러나 IVIg 의유용성이예상되면서도아직확증되지못한다른자가면역성신경근질환들에서도앞으로많은연구가이뤄질것이다. 또한 IVIg 의유지용량, 투여빈도, 다른치료법과의병용요법에 따른효과등의정확한기준이아직확립되지않은바향후이에관하여더연구가되어야할것이다. REFERENCES 01. Dalakas MC. The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular disease: evidence-based indication and safety profile. Pharmacology & Therapeutics 2004;102: Nobile-Orzion E, Trenghi F. IVIg in idiopathic autoimmune neuropathies: analysis in the light of the latest results. J Neurol. 2005;252:S Dwyer JM. Manupulating the immune system with immune globulin. N Engl J Med 1992;326: schiff R.J. Transmission of viral infections through intravenous immune globulin. N Engl J Med 1994;331: Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994; 121: Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K. Treatment of inclusion body myositis with IVIG: a double-blind, placebo-control study. Neurology 1997;48: Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular disease. JAMA. 2004;291: Tankersley DL, Preston MS, Finlayson JS. Immunoglobulin G dimmer: an idiotype-anti-idiotype complex. Mol Immunol 1988;25: Kazatchkine MD, Dietrich G, Hurez V, Ronda N, Bellon B, Rossi F, et al. V region-mediated selection of sutoreactive repertoires by intravenous immunoglobulin. Immunol Rev 1994;139: Malik U, Oleksowicz L, Latov N, Cardo LJ. Intravenouus y-globulin inhibits binding of anti-gm1 to its target antigen. Ann Neurol 1996;39: Kaveri S, Prasad N, Vassilev T, Hurez V, Pashov A, Lacroix-Desmazes S, et al. Modulation of autoimmune response by intravenous immunoglobulin. Mult Scler 1997;3: Dietrich G, Kazatchkine MD. Normal immunoglobulin G (IgG) for therapeutic use (intravenous Ig) contains antiidiotypic specificities against an immunodominant, disease-associated, cross-reactive idiotype of human anti-thyroglobulin autoantibodies. J Cliin Invst 1990;85: Buchwald B, Ahangari R, Weishaupt A, Toyka KV. Intravenous immunoglobulins neutralize blocking antibodies in Guillain-Barre Syndrome. Ann Neurol 2002;51: Diegel M, Rankin B, Bolen J, Dubois P, Kiener P. J Korean Society for Clinical Neurophysiology / Volume 8 / June,

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10 말초신경병증에대한정맥내면역글로불린요법 Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Gullain-Barre syndrome. N Engl J Med 1992;326: Plasma Exchange/Sandoglobulin Gullain-Barre Syndrome Trial Group. Randomized trial of plasma exchange, intravenous immunoglobulin, and plasma exchange followed by intravenous immunoglobulin in Gullain-Barre syndrome. Lancet 1997;349: Arakawa Y, Yoshimura M, Kobayashi S, Ichihashi K. The use of intravenous immunoglobulin in Miller-Fisher syndrome. Brain Dev 1993;15: Raphael JC, Chevret S, Harboun M, Jars-Guineestre MC. Intravenous immune globulins in patients with Gullain- Barre syndrome and contraindications to plasma exchange:3 day versus 6 day. J Neurol Neurosurg Psychiatry 2001;71: Romano JG, Rotta FT, Potter P, Rosenfeld V, Santibanez R, Rocha B, et al. Relapses in the Gullain-Barre syndrome after treatment with intravenous immune globulin or plasma exchange. Muscle Nerve 1998;21: Farcas P, Avnun L. Frisher S, Herishanu YO, Wirguin I. Efficacy of repeated intravenous immunoglobulin in severe unresponsive Gullain-Barre syndrome. Lancet 1997;350: Kuwabara S, Asahina M, Koga M, Mori M, Yuki N, Hattori T. Two patterns of clinical recovery in Gullain- Barre syndrome with IgG anti-gm1 antibody. Neurology 1998;51: Rees JH, Gregson NA, Hughes RAC. Antiganglioside antibodies in Gullain-Barre syndrome and their relationship to Camphylobacter jejuni infection. Ann Neurol 1995;38: Hughes R, Bensa S, Willison H, Van den Bergh P, Comi G, Illa I, et al. Rnadomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory Demyelinating polyradiculoneuropathy. Ann Neurol 2001;50: Hahn AF, Bolton CF, Zochodne D, Feasby TE. Intravenous immunoglobulin treatment in chronic inflammatory Demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study. Brain 1996;119: Vermeulen M, van Doorn PA, Brand A, Strnger PFW, Jennekens FGI, Busch HGM. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. J Neurol Neurosirg Psychiatry 1992;56: Van den Berg-Vos RM, Franssen H,Wokke JH, Van den Berg LH. Multifocal motor neuropathy: long-term clinical and electrophysiological assessment of intravenous immunoglobulin maintenance treatment. Brain 2002;125: Dalakas MC, Quarles RH, Farrer RG, Dambrosia J, Soueidan S, Stein DP, et al. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol 1996;40: Dalakas, M. C. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 1999;22: Kurlander RJ, Hall J. Comparison of intravenous gammaglobulin and a monoclonal anti-fc receptor antibody as inhibitors of immune clearance in vivo in mice. J Clin Invest 1986;77: Bertorini TE, Nance AM, Horner LH, GreeneW, Gelfand MS, Jaster JH. Complications of intravenous gammaglobulin in neuromuscular and other diseases. Muscle Nerve 1996;19: Dalakas MC, Clark WM. Strokes, thromboembolic events, and IVIg: rare incidents blemish an excellent safety record. Neurology 2003;60: Burks AW, Sampson HA, Buckley RH. Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia. N Engl J Med 1986;314: Ahsan N. Intravenous immunoglobulin induced-nephropathy: a complication of IVIg therapy. J Nephrol 1998;11: J Korean Society for Clinical Neurophysiology / Volume 8 / June,