대한임상신경생리학회지 8(1):48~52, 2006 ISSN 1229-6414 건양대학교의과대학신경과학교실, 연세대학교의과대학신경과학교실 나상준 최영철 Adverse Events Associated with Intravenous Immunoglobulin Therapy in Neuromuscular Disorders Sang-Jun Na, M.D. Young-Chul Choi, M.D.* Department of Neurology, Konyang University, College of Medicine Department of Neurology*, Yonsei University, College of Medicine Background: Intravenous immunoglobulin (IVIg) has been administered for various immune-mediated neurological diseases such as autoimmune neuropathy, inflammatory myopathies, and other autoimmune neuromuscular disorders. The purpose of this study is to investigate side effects and complications of IVIg therapy in neuromuscular disorders. Methods: We enrolled 29 patients (age 8~63 years) with IVIg therapy for various neurological diseases including Guillain-Barre syndrome, myasthenia gravis, dermatomyositis, polymyositis, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy. IVIg therapy was used at a dose of 0.4 g/kg body weight/day for 5 consecutive days. Results: 10 patients (34%) had adverse events. There are adverse events in 16 courses (11%) among total 145 courses. The majority of patients presented with mild side effects, mostly asymptomatic laboratory changes. Rash or mild headache occurred in 3 patients. One patient showed a serious side effect of deep vein thrombosis. Conclusions: IVIg therapy is safe for a variety of immune-mediated neurological diseases in our study. Key Words: Intravenous immunoglobulin therapy, Adverse event 서 론 정맥내면역글로불린 (intravenous immunoglobulin, IVIg) 은초기에특발성혈소판감소성자반증이나카와사키증후군과같은자가면역질환에주로사용되었다. 1-3 이후로그영역이확대되어최근에는자가면역성신경계질환인길랑 - 바레증후군, 만성염증성탈수초성말초신경병 Address for correspondence; Young-Chul Choi, M.D., Ph.D. Department of Neurology, Yongdong Severance Hospital, Yonsei University College of Medicine, 146-92 Gangnam-gu, Seoul 135-720, Korea Tel: +82-2-2019-3323 Fax: +82-2-3462-5904 E-mail: ycchoi@yumc.yonsei.ac.kr This work was supported by brain Korea 21 project for Medical Sience Yonsei University and Dong Shin pharm. Co. LTD. 증, 중증근무력증, 다발성경화증등에사용되고있다. 4,5 현재까지 IVIg 치료효과가확립된신경근질환은만성염증성탈수초성말초신경병증, 6 길랑 - 바레증후군, 7 다초점운동신경병증, 8 중증근무력증, 9 람버트이튼증후군, 10 다발성경화증, 11 피부근염, 12 봉입체근염 13 및 stiff-person syndrome 14 등이다 (Table 1). IVIg 의작용기전으로 Fc 수용체매개효과, 보체 (complement) 의조절, 사이토카인생성조절, 초항원 (superantigen) 의중화, 항인자형항체 (antiidiotypic antibody) 에의한자기항체중화, 면역글로불린의대사항진을유도하거나 T 임파구의기능과항체의인식조절등이알려져있다. 15-17 IVIg 치료시발생할수있는부작용중근육통, 두통, 발열또는무증상실험결과변화 (asymptomatic laboratory change) 와같은경한부작용은 11% 에서 81% 로광범위하다고알려져있다. 18,19 반면뇌졸중, 20 신부전, 21 무 48 Copyright 2006 by the Korean Society for Clinical Neurophysiology
균성뇌막염 22 또는간염 5 등의심각한합병증은드물게보고되고있다. 최근우리나라에서도다양한신경과질환에서 IVIg 치료를시행하고있으나발생부작용및합병증에대한연구보고가전무한상태이다. 따라서본연구에서는신경과질환에서고용량정맥내면역글로불린치료시발생할수있는부작용및합병증을알아보고자하였다. 대상과방법 2003 년 1 월부터 2005 년 12 월까지건양대병원신경과와영동세브란스병원신경과에입원한환자들중 IVIg 를사용한 29 명을대상으로하였으며환자챠트를리뷰하는후향적연구로진행하였다. 대상환자는 IVIg 치료효과가확립되어진길랑 - 바레증후군, 만성염증성탈수초성말초신경병증, 다초점운동신경병증, 중증근무력증, 람버트이튼증후군, 다발성경화증, 피부근염, 봉입체근염및 stiff-person syndrome 과일부보고되어진다발성근염, 당뇨병성근위축증및 Bickerstaff 뇌간뇌염등의신경과적질환에국한시켰다 (Table 1). 면역글로불린 A 결핍증환자, 신장애가있는환자, 용혈성빈혈환자, 면역부전환자및면역력이억제된환자들은연구에포함시키지않았다. 치료에사용된 IVIg 는인간면역글로불린 ( 리브감마주, 동신제약 ) 을사용하였고하루에 0.4g m/kg 의용량으로정주하였고정주속도는시간당 2.5~5 gm 으로하였으며, 연속적으로 5 일간투여하였다. IVIg 치료시작하기전에혈액검사, 일반화학검사, 소변검사및체온을측정하였고또한매번일련의 IVIg 투여가끝난후혈액검사, 일반화학검사, 소변검사및체온을측정하였다. IVIg 치료효과는 van Doorn PA 등이만성염증성탈수초성말초신경병증에서의 IVIg 치료효과평가에사용했던 Modified Rankin score (MRS) 를이용하였다. 6 치료전과치료후 2 주까지의 MRS 등급을비교하여등급이 1 이상감소할경우를효과가있는것으로평가하였다. 부작용및합병증은경한경우와심각한경우, 두가지로나누었다. 18 생명에위협이없는증상들과무증상실험결과변화들은경한부작용에포함시켰고생명에위협을주는경우들을심각한부작용에포함시켰다. 결 과 본연구에포함된환자는전체 29 명으로, 질환의분포는길랑 - 바레증후군 (15 명 ), 중증근무력증 (5 명 ), 피부근염 (3 명 ), 다발성근염 (3 명 ), 만성염증성탈수초성말초신경병증 (2 명 ), 및다초점운동신경병증 (1 명 ) 이었다 (Table 2). 환자의평균연령은 38.4 세 ( 범위 ;8~63 세 ) 였으며남녀의비율은 15:14 로거의같았다. 29 명의환자가 IVIg 치료를 총 145 과정으로받았으며치료효과는 23 명 (79%) 에서증상의개선이보였다. 29 명중 10 명 (34%) 에서부작용이관찰되었다 (Table 3). 두통, 오한및발열은 IVIg 치료직후또는주사동안각각 2 명, 1 명및 1 명이발생하였다. 두드러기및손바닥가려움증과같은피부반응은 1 명의환자에서 IVIg 정주후 5 일째발생하여증상이 2 주동안지속되었으며항히스타민제재를 1 주사용한후완전히회복되었다. IVIg 치료에의해부작용이발생한 10 명중 7 명에서무증상실험결과변화를가진경한부작용이관찰되었다. 당뇨 (glucosuria) 및적혈구침강속도상승은각각 1 명, 7 명에서관찰되었으며모두주사후 24 시간이내에발생하였다. 혈액내호중구감소는관찰되지않았다. 전신에근력저하가있었던 56 세중증근무력증여자환자에서심부정맥혈전증이 IVIg 치료 3 일째발생하였다. 임상양상, 초음파검사, 및혈액검사에서 D-dimer 상승에의해심부정맥혈전증을진단하였다. 환자에게서초기에헤파린으로정맥투여하였고이후에경구용항혈소판제재를사용하였다. 총 145 치료과정에서부작용의발생빈도는 16 과정으로 11% 였고이중경한부작용은 15 과정 (10.3%) 에서발생하였으며심각한부작용은 1 과정 (0.7%) 에서발생하였다. 고 찰 최근보고들에의하면 IVIg 치료는효과적이고안전한절차로알려져있지만부작용들의빈도는 11% 에서 81% 로그범위가다양하다. 본연구에사용된 IVIg 은액상으로동결건조된형태보다더편리하고사용하기쉬우며부작용이덜발생한다. 심각한부작용들은환자들중단지 4.5%~16 Table 1. Indications for IVIg therapy in neuromuscular disorders according to the literatures Randomised controlled studies Chronic inflammatory demyelinating polyneuropathy 6 Guillain-Barre syndrome 7 Multifocal motor neuropathy 8 Myasthenia gravis 9 Lambert-Eaton syndrome 10 Relapsing-remitting multiple sclerosis 11 Dermatomyositis 12 Inclusion body myositis 13 Stiff-person syndrome 14 Case reports or open studies Polymyositis 36 Diabetic amyotrophy 37 Bickerstaff s brainstem encephalitis 38 J Korean Society for Clinical Neurophysiology / Volume 8 / June, 2006 49
나상준 최영철 Table 2. Clinical Data of the 29 patients Patient No. (Sex/Age) Diagnosis IVIg (Total) Outcome 01 (M/41) GBS 2g Improvement 02 (M/56) GBS 2g No improvement 03 (M/40) GBS 2g Improvement 04 (F/24) GBS 2g Improvement 05 (F/54) GBS 2g Improvement 06 (F/53) GBS 2g Improvement 07(M/47) GBS 2g Improvement 08 (F/25) GBS 2g Improvement 09 (M/52) GBS 2g Improvement 10 (M/34) GBS 2g Improvement 11 (F/63) GBS 2g Improvement 12 (F/33) GBS 2g Improvement 13 (M/44) GBS 2g Improvement 14 (M/52) GBS 2g No improvement 15 (F/32) GBS 2g Improvement 16 (M/36) MG 2g Improvement 17 (M/25) MG 2g Improvement 18 (F/56) MG 2g No improvement 19 (F/54) MG 2g No improvement 20 (F/32) MG 2g Improvement 21 (F/13) DM 2g Improvement 22 (F/8) DM 2g Improvement 23 (F/12) DM 2g Improvement 24 (M/28) PM 2g No improvement 25 (M/18) PM 2g Improvement 26 (F/22) PM 2g Improvement 27 (M/57) CIDD 2g Improvement 28 (M/62) CIDP 2g No improvement 29 (M/42) MMN 2g Improvement GBS; Guillain-Barre syndrome, MG; Myasthenia gravis, DM; Dermatomyositis, PM; Polymyositis, MMN; Multifocal motor neuropathy, CIDP; Chronic inflammatory demyelinating polyneuropathy Table 3. Side effects in 29 patients with IVIg therapy Side effects 145 courses (%) 29 Patients (%) Mild side effects Elevated blood sedimentation time 8 (5.6) 7 (24.1) Neutropenia 0 0 Glucosuria 1 (0.7) 1 (03.4) Headache 3 (2.1) 2 (06.8) Chills 1 (0.7) 1 (03.4) Fever 1 (0.7) 1 (03.4) Skin reactions 1 (0.7) 1 (03.4) Serious side effects 1 (0.7) 1 (03.4) Deep vein thrombosis 0 0 Stroke 0 0 Renal failure 0 0 Aseptic meningitis 0 0 Hepatitis 0 0 50 J Korean Society for Clinical Neurophysiology / Volume 8 / June, 2006
% 에서나타난다고알려져있다. 18,19 본연구에서는경한부작용과심각한부작용을포함한전체부작용이발생한빈도는 34% 였고심각한부작용이발생한빈도는 3.4% 였다. 부작용들중무증상실험결과변화가가장흔하게나타났다. 당뇨 (glucosuria) 는혈당증가에의해나타나는것으로보여지며혈당증가는면역글로불린제재중당을포함한안정제에의한것으로생각되고있다. 가성저나트륨혈증은단백과잉혈증에의해생긴실험적인공물로써설명되며 23 본연구에서는관찰되지않았다. 두통, 오한, 근육통, 가슴통증및발열은 IVIg 정주하는동안또는정주후에나타나지만대개자발적으로호전된다. 이러한부작용들은보통급속한정주속도때문이다. 24 독감유사증후군의원인은아직까지잘모르지만면역글로불린제재안에있는무리면역글로불린분자 (aggregated immunoglobulin molecules) 또는다양한안정제에의한보체의활성화가그원인으로제시되고있다. 25 두드러기, 손바닥가려움증및사지점출혈과같은피부부작용은 IVIg 정주후 2~5일에발생하며약 1개월에서 6개월까지지속된다는보고들이있다. 26,27 가려움증과근육통은 TNF-a에의해나타날것으로생각되며본연구에서는 1명의환자에서이런증상이나타났으며양성과정을보였다. 정상적으로피부부작용은생명에위협을주지않지만상당한불편함을유발한다. IVIg와스테로이드복합요법이피부부작용을예방할수있다고알려져있으나아직은논란이많다. 26,27 피부부작용해결을위해 IVIg의일시적인중단이나용량감소가제안되고있다. 27-29 두통은 IVIg 치료를받은환자의 5% 미만에서보이지만어떠한연구에서는 48% 까지발생한다고 30,31 하며가장흔한부작용으로믿어진다. 19 심한두통, 광선공포증또는발열을보이는무균성뇌막염의빈도는 11% 에서관찰되며이경우때때로뇌척수액검사에서백혈구증가증, IgG 증가가동반된다. 편두통을가지고있던환자에서 IVIg 치료시무균성뇌막염의빈도가높다고 22 알려져있지만원인은아직까지모른다. 32 본두통발생빈도는 6.8% 로매우흔하지는않았다. IVIg 치료후뇌졸중이발생하는경우가있는데 31 이는 IVIg 치료를받는환자의심혈관또는혈액학적상태뿐만아니라 IVIg 정주로인한혈액점도의상승과혈액량팽창때문이다. 33 본연구에서는부작용으로뇌졸중이관찰되지않았다. 당함량과신부전과관계가있는데 IVIg 관련신기능이상의 90% 는자당 (sucrose) 을포함한조제품에의한것이다. 34 본연구에사용된 IVIg는 10% 맥아당 (maltose) 을포함하고있었다. 나트륨함량이높을수록혈전성및색전성합병증들이나타날확률이높다. 35 본연구에사용된 IVIg는나트륨을포함하고있지않았다. IVIg 치료후심부정맥혈전증이발생할수있으며, 32 특히환자의움직임이고정된상태인경우혈전증의고위험군이며 IVIg 치료가혈액점도를높여혈전성사건들을일으킬가능성이높아진다. 따라서 IVIg 치료시심부정맥혈전증을예방하기위하여저용량의헤파린이도움이될수있다. 결론적으로 29 명의 IVIg 치료를받은환자들중심각한부작용이발생한경우는 1 명으로대부분의경우부작용이없거나경한부작용들이관찰되었다. 따라서본연구에서는 IVIg 치료가다양한면역매개신경과질환들에효과가있으며또한안전하다는것을알수있었다. REFERENCES 01. Imbach P, Barandun S, d Apuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981;1:1228-1231. 02. Berkman SA, Lee ML, Gale RP. Clinical uses of intravenous immunoglobulins. Ann Intern Med 1990;112:278-292. 03. Dwyer JM. Manipulating the immune system with immune globulin. N Engl J Med ;326:107-116. 04. Wiles CM, Brown P, Chapel H, et al. Intravenous immunoglobulin in neurological disease: a specialist review. J Neurol Neurosurg Psychiatry 2002;72:440-448. 05. Stangel M, Hartung HP, Marx P, Gold R. Side effects of highdose intravenous immunoglobulins. Clin Neuropharmacol 1997;20:385-393. 06. van Doorn PA, Brand A, Strengers PF, Meulstee J, Vermeulen M. High-dose intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a doubleblind, placebo-controlled, crossover study. Neurology 1990;40:209-212. 07. Van der Meche FG, Schmitz PI. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. Dutch Guillain-Barre Study Group. N Engl J Med 1992;326:1123-1129. 08. Van den Berg LH, Kerkhoff H, Oey PL, et al. Treatment of multifocal motor neuropathy with high dose intravenous immunoglobulins: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry 1995;59:248-252. 09. Drachman DB. Myasthenia gravis. N Engl J Med1994;330 :1797-1810. 10. Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1996;47:678-683. 11. Sorensen PS. Treatment of multiple sclerosis with intravenous immunoglobulin: review of clinical trials. Neurol Sci 2003;24 Suppl 4:S227-230. 12. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial J Korean Society for Clinical Neurophysiology / Volume 8 / June, 2006 51
나상준 최영철 of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med1993;329:19 93-2000. 13. Walter MC, Lochmuller H, Toepfer M, et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol 2000;247:22-28. 14. Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001;345:1870-1876. 15. Emmi L, Chiarini F. The role of intravenous immunoglobulin therapy in autoimmune and inflammatory disorders. Neurol Sci 2002;23:S1-S8. 16. Ballow M. Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory diseases. J Allergy Clin Immunol 1997;100:151-157. 17. Dalakas MC. Mechanism of action of intravenous immunoglobulin and therapeutic considerations in the treatment of autoimmune neurologic diseases. Neurology 1998;51:S2-S8. 18. Brannagan TH 3rd, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin treatment in neurologic disease. Neurology 1996;47:674-677. 19. Bertorini TE, Nance AM, Horner LH, Greene W, Gelfand MS, Jaster JH. Complications of intravenous gammaglobulin in neuromuscular and other diseases. Muscle Nerve 1996;19:388-391. 20. Silbert PL, Knezevic WV, Bridge DT. Cerebral infarction complicating intravenous immunoglobulin therapy for polyneuritis cranialis. Neurology 1992;42:257-258. 21. Tan E, Hajinazarian M, Bay W, Neff J, Mendell JR. Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol 1993;50:137-139. 22. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994;121:259-262. 23. Lawn N, Wijdicks EF, Burritt MF. Intravenous immune globulin and pseudohyponatremia. N Engl J Med1998;339 :632. 24. Stangel M, Hartung HP, Marx P, Gold R. Intravenous immunoglobulin treatment of neurological autoimmune diseases. J Neurol Sci 1998;153:203-214. 25. Dalakas MC. Intravenous immune globulin therapy for neurologic diseases. Ann Intern Med 1997;126:721-730. 26. Hamdalla HH, Hawkes CH, Spokes EG, Bamford JM, Goulding PJ. Intravenous immunoglobulin in the Guillain- Barre syndrome. May cause severe adverse skin reactions. BMJ 1996;313:1399-1400. 27. The Dutch Guillain-Barre Study Group. Treatment of Guillain-Barre syndrome with high-dose immune globulins combined with methylprednisolone: a pilot study. The Dutch Guillain-Barre Study Group. Ann Neurol 1994;35:7 49-752. 28. Whittam LR, Hay RJ, Hughes RA. Eczematous reactions to human immune globulin. Br J Dermatol 1997;137:481-482. 29. Sorensen PS, Wanscher B, Jensen CV, et al. Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 1998;50:1273-1281. 30. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-226. 31. Steg RE, Lefkowitz DM. Cerebral infarction following intravenous immunoglobulin therapy for myasthenia gravis. Neurology 1994;44:1180-1181. 32. Go RS, Call TG. Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: Case report and literature review of intravenous immunoglobulin-related thrombptic complication. Mayo Clin Proc 2000;75:83-85. 33. Plasma Exchange/Sandoglobulin Guillain-Barre Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barre syndrome. Lancet 1997;349:2 25-230. 34. Renal insufficiency and failure associated with immune globulin intravenous therapy. MMWR 1999;48:1985-1998. 35. Nydegger UE, Sturzenegger M. Adverse effects of intravenous immunoglobulin therapy. Drug Saf 1999;21:171-185. 36. Cherin P, Pelletier S, Teixeira A, et al. Results and longterm followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum 2002;46:467-474. 37. Fernandes Filho JA, Nathan BM, Palmert MR, Katirji B. Diabetic amyotrophy in an adolescent responsive to intravenous immunoglobulin. Muscle Nerve 2005;32:818-820. 38. Fox RJ, Kasner SE, Galetta SL, Chalela JA. Treatment of Bickerstaff s brainstem encephalitis with immune globulin. J Neurol Sci ;178:88-90. 52 J Korean Society for Clinical Neurophysiology / Volume 8 / June, 2006