ISSN 2092-5077 Korean Journal of Neuromuscular Disorders Vol. 2, July 2010 봉입체근육염 연세대학교의과대학신경과학교실 서경임 홍지만 최영철 Inclusion Body Myositis Gyoungim Suh, MD, Ji-Man Hong, MD, Young-Chul Choi, MD, PhD Department of Neurology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea KEYWORDS Inclusion body myositis, Sporadic inclusion body myositis, Idiopathic inflammatory myositis, Muscle biopsy Inclusion body myositis (IBM) is the most common idiopathic inflammatory myositis in patients over the age of 50 years. Prevalence of IBM varies among countries and ethnic groups. Etiology and pathogenesis of IBM is still unknown. It may be primary degenerative myopathy or autoimmune inflammatory myopathy or both. Asymmetrical weakness of the quadriceps and flexor forearm muscles are the clinical key of IBM. This review covers clinical presentation, pathogenesis, diagnosis and treatment of IBM. 서론 특발성염증성근육병에는피부근육염, 다발근육염, 봉입체근육염이있고그중봉입체근육염은 50세이상의성인에서가장호발하는후천성근육병이다. 봉입체근육염 (inclusion body myositis) 이라는용어는 Yunis와 Smamha에의해 1971년처음으로사용되었고, 1 유병률은국가와인종에따라다양하며남자가여자보다많다. 봉입체근육염은중년이후에발생하는긴손가락굽힘근과넙다리네갈래근의위약으로시작하는독특한양상의염증성근육염이다. 우리나라에서는정확한통계자료가없으나그발생률이증가하고있는것으로추정된다. 네덜란드에서백만명당 4.9명, 2 호주에서 14.9명 3 의유병률로보고되었고, 그중 50 세이상에서는백만명당 16명 2 ~51.3명 3 의유병률을보이며 과거보다증가하고있다. 발생연령은 30세이상이고 50세이후에호발하며스테로이드등의면역치료에효과가없는것이특징이다. 본고에서는병인, 병태생리, 임상양상, 검사소견, 감별질환을비롯해봉입체근육염에대한전체적인이해를돕기위한내용을풀어나가고자한다. 본론 1. 임상양상 봉입체근육염은주로 50세이후에발생하며, 4 30대이후에도발생할수있다. 증상은비교적서서히발생하여천천히진행한다. 특징적인근육위약의양상이중요하며, 다 Received June 11, 2010 / Accepted June 21, 2010 Address for correspondence: Young-Chul Choi, MD, PhD Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, 712 Eonjuro, Gangnam-gu, Seoul 135-720, Korea Tel: +82-2-2019-3323, Fax: +82-2-3462-5904, E-mail: ycchoi@yuhs.ac Korean Journal of Neuromuscular Disorders 2010 21
Korean Journal of Neuromuscular Disorders Vol. 2, 2010 른염증성근육염들이상하지의근위부위약이두드러지는데비해하지의넙다리네갈래근과손의긴손가락굽힘근을침범하는점이특징적이어서, 낮은의자에서일어나는것이힘들어지거나잘넘어지는경향을보이고손을꽉쥐거나손가락을이용한세밀한동작들이안되는것을호소한다. 위약감은비대칭적으로나타나는경우가흔하다. 넙다리네갈래근과아래팔의위축을호소할수도있는데, 아래팔의위축과위약은비우세팔에서두드러지는경향을보인다. 5 질병의초기에는흔하지않으나질병이진행되면서 3분의 2가량에서연하곤란이나타났다는보고가있고, 6 경미한얼굴의위약도흔히있으나질병후기에도외안근은보존된다. 7 전신홍반루프스, 8 쇠그렌증후군, 9 피부경화증 10 과같은자가면역질환과동반된예들이보고되었다. 2. 병인과병태생리, 병리소견 봉입체근육염의가장근본적인병인이무엇인지에대한연구가이루어지고있으며면역, 유전, 노화, 환경적유발이복합적으로작용할것이라생각되나정확한병인은밝혀지지않았다. 가장중요한발생기전으로는면역매개성염증성근육병증이란주장이있다. 이에따르면다발근육염에서와같이주로 T 림프구에의해매개되는자가면역반응이일어나근육섬유를손상시키고이후이차적으로근육섬유의퇴행성변화를일으킨다고생각하고있다. 11 이를뒷받침하는근육생검소견들이있는데, 질병의초기에염증반응이심하고, 공포성변화는질병후기에두드러진다는점, 12,13 CD8+T 림프구에의해침윤된비괴사성근섬유가 rimmed vacuole을포함하거나아밀로이드를포함한근섬유보다흔하다는점이다. 14 면역조직화학염색을했을때건강한근섬유에서 MHC-1이과발현되어있는것도 15 염증반응이근본적인기전임을뒷받침한다. 다른의견으로는일차적인기전으로근육섬유안에비정상단백질의침착물 (deposit) 과연관된퇴행성과정이있고이차적으로이에대한자가면역성염증변화가일어난다고보는경우가있다. 16 혹은, 앞의두과정이서로독립적으로작용한다고보는의견도있다. 일부 HIV나 17 HTLV 의감염과관련되어 18 봉입체근육염이발생한예가있어바이러스감염이자가면역반응의시동을걸었을가능성을보여주지만대부분의봉입체근육염환자는뚜렷한선행감염이나환경적유발요인없이발병한다. 최근들어병태생리에있어서유전적인자가미치는영향에대한관심이증가하고있는데, 항원발현에관여하는 class II MHC 단백을 코딩하는 MHC 유전자의다형태 (polymorphism) 에따라자가항원에대한내성의정도가다르거나, 면역조절과 T 림프구활성화에관여하는유전적소인이다른것이질병유발의원인이될수있다고보고한연구도있다. 19 3. 진단 혈청크레아틴키나제는정상수치의 10배이내로증가되어있으나정상일수있고약간올라가있는경우도있다. 근전도에서는자발전위가증가되어있으며근육병성, 신경병성전위가혼재되어있는것이특징이다. 비정상적자발전위 (fibrillation potentials, positive sharp wave) 와신경인성 MUAP (long duration high amplitude MUAP) 때문에자칫운동신경원질환으로오인될수있어 20,21 주의해야한다. 근육컴퓨터전산단층촬영이나자기공명영상촬영은증상이시작된지얼마되지않은초기의증례나비전형적인임상양상을나타내는경우에하지의넙다리네갈래근, 안쪽장딴지근이나팔의전완부굽힘근의특징적인근육의침범을확인함으로써진단에도움이될수있다. 22,23 봉입체근육염진단을하기위해서는근육생검이필수적이다. 생검을위한근육은일차적으로가쪽넓은근 (vastus lateralis) 을고려하지만위축이심하게되었을경우에는삼각근, 위팔두갈래근을선택할수있다. 봉입체근육염에서근육생검소견은다음과같이나타날수있다. 첫째, 만성적근육병적변화가보인다. 비대한근섬유, 위축된근섬유, 쪼개진근섬유가내핵의증가및교원섬유의증가와동반되어있다. 둘째, endomysial 염증세포의침윤이다발성으로존재한다. CD8+T 림프구가괴사되지않은근섬유주변을침범하고있고, MHC-I이괴사된혹은괴사되지않은근섬유에표현되어있다. 셋째, rimmed vacuole, 과립성물질 (granular material) 과과립성미세섬유 (granular filaments) 가보인다. 염기성의과립성봉입체가 slit-like vacuole의언저리에있다. 넷째, 아밀로이드의침착물이생기며이는콩고레드염색에서가장잘보인다. Beta amyloid, 24 desmin, ubiquitin, tau, prion, transglutaminases 1&2 25,26 등의단백질이보인다. 다섯째, 시토크롬산화효소 (cytochrome oxidase) 와사립체유전자변이가없음에도 red ragged fibers와같은비정상적미토콘드리아가보인다. 여섯째, 전자현미경에서세포질안이나핵안에 15~18 nm tubulofilamentous inclusion이보인다. 상기소견들은봉입체근육염에특이한것은아니나진 22 대한신경근육질환학회지 2010
단에는필수적인소견이다. 같은특발성염증성근육염인피부근육염에서는눈꺼풀, 얼굴, 무릎, 팔꿈치, 목, 앞가슴의연보라발진 (heliotrope rash) 이나 Gottron 징후 (Gottron rash) 등의피부병변의유무로임상양상에서쉽게감별이가능하며근육병리소견에서도다발주변위축 (perifascicular atrophy) 과같이피부근육염에특이한양상을확인함으로써감별할수있다. 다발근육염은봉입체근육염으로흔히잘못진단되는데봉입체근육염에서상대적으로고령에발병하고, 침범되는근육의양상이특이하며, 근육섬유에아밀로이드가침착되는점, 스테로이드에반응이없는점으로구분될수있다. 특히봉입체근육염을진단하는데에는근육생검의병리소견이중요한데, 염증성근육병의소견은있으나 Rimmed vacuole 이나 congophilic myofiber deposit은결핍되어있는경우는 possible 봉입체근육염진단기준 4 과 probable 봉입체근육염진단기준 27 에해당되고다발근육염진단기준 28 에해당되지않음에도불구하고이전에는다발근육염으로진단되는경우가많았다. 한후향적소규모연구에의하면 rimmed vacuole, 아밀로이드침착물이관찰되지않았으나임상적으로봉입체근육염양상을보였던환자군에서면역억제치료에증상호전은없었고오직 29% 만이안정화된데비해전형적인다발근육염의양상을보인환자는면역억제치료에모두호전혹은안정을보였다. 29 국내에서병리소견과임상양상에기반해진단된다발근육염환자군에서도 74% 에서호전을보였다. 30 봉입체근육염의진단기준은 1995년 Griggs 등이처음제안하였고 4 수정안을 2002년에제안하였다 (Table 1). 31 수정된진단기준에따르면 rimmed vacuole이나아밀로이드침착물과같이질병의초기에나타나지않을수있는병리소견이없다고해도특징적인위약과봉입체근육염의임상양상을가진환자들을봉입체근육염의진단에서배제해서는안된다 12,32. 그외에봉입체근육염과감별을요하는질병들에는유전성봉입체근육염 (hereditary inclusion body myositis), Welander 원위부근육병, 정강근이영양증 (tibial muscular dystrophy) Table 1. 31 Diagnostic classification and characteristic features of inclusion body myositis (IBM) I. Diagnostic classification A. Definite IBM 1. invasion of nonnecrotic fibers by mononuclear cells 2. vacuolated muscle fibers 3. intracellular (within muscle fibers) amyloid deposits or 15~18 nm tubulofilaments Patients must exhibit all muscle biopsy features. None of the other clinical or laboratory features are mandatory if muscle biopsy features are diagnostic. B. Probable IBM 1. invasion of nonnecrotic fibers by mononuclear cells 2. vacuolated muscle fibers 3. intracellular (within muscle fibers) amyloid deposits or 15~18 nm tubulofilaments If the muscle shows pathologic features (B1,2) but without amlyoid deposits or tubulofilaments, then a diagnosis of probable inclusion body myositis can be given if the patient exhibits the characteristic clinical (A1,2,3) and laboratory (B1,3) features. II. Characteristic features A. Clinical features 1. Duration of illness > 6 months 2. Age of onset > 30 years of age 3. Muscle weakness Must affect proximal and distal muscles of arms and leg and Patient must exhibit at least one of the following features: a. Finger flexor weakness b. Wrist flexor > wrist extensor weakness c. Quadriceps muscle weakness B. Laboratory features 1. Serum creatine kinase < 12 times upper limit of normal 2. Muscle biopsy a. Inflammatory myopathy characterized by mononuclear cell invasion of nonnecrotic muscle fibers b. Vacuolated muscle fibers c. Either (1) Intracellular amyloid deposits (must use fluorescent method of identification before excluding the presence of amyloid) or (2) 15 18 nm tubulofilaments by electron microscopy 3. Electromyography must be consistent with features of an inflammatory myopathy (however, long-duration potentials are commonly observed and do not exclude diagnosis of sporadic inclusion body myositis). Korean Journal of Neuromuscular Disorders 2010 23
Korean Journal of Neuromuscular Disorders Vol. 2, 2010 등의원위부근육병, 운동신경원질환이있다. 유전성봉입체근육염의경우근육병리소견에서 rimmed vacuolous filamentous inclusion이흡사하나, 염증성변화와 MHC-1의발현의증가가관찰되지않는다. GNE 유전자변이에서기인하며 DMRV (Distal myopathy with rimmed vacuole) 로도불리운다. 초기에원위부하지앞부분부터위약이나타나고, 혈청크레아티닌키나제는중등도로증가하고봉입체근육염에서특징적으로침범하는넙다리네갈래근이보존된다. Welander 원위부근육병과정강근이영양증은근육병리소견에서공포성근육병이지만염증이없다. 근위부침범이 Welander 원위부근육병에서드물고정강근이영양증에서는매우늦게나타나고두질병모두긴손가락폄근의위약으로증상이시작되므로임상양상에서봉입체근육염과구별된다. 운동신경원질환과임상양상에서혼동되는경우가있으나근육병리소견으로감별이가능하다. 4. 치료 봉입체근육염은다발근육염에서처럼 T 림프구를매개로한자가면역뿐아니라퇴행성병리기전을가지고있는복합적인질병이다. 현재까지 9개의무작위임상시험이소규모의봉입체근육염환자군을대상으로면역글로불린, beta-interferon, methotrexate, oxandrolone, azathioprine의치료효과에대한연구가이루어졌으나유의한효과를입증한연구는없었다. 33 스테로이드는전형적인봉입체근육염에비해진행이빠르고염증반응이두드러지게보이는진단적으로의심이되는환자들에서더사용되고있다. 부가적인 coenzyme Q10과운동혹은 methotrexate, azathioprine이사용될때도있다. 면역글로불린은빨리진행되는증례나연하곤란을두드러지게호소하는경우에사용되는경향이있다. 결론 봉입체근육염은 50세이상성인의특발성염증성근육병의가장흔한유형으로서양에서더유병률이높지만한국인을포함한아시아에서도증가하고있는질병이다. 근육병리소견이봉입체근육염의진단에있어가장중요한방법이지만넙다리네갈래근의위약과긴손가락굽힘근의위약으로나타나는특징적인임상양상이중요하며중년이후의위약감을호소하는환자들에서다발근육염으로진단을내리기전에봉입체근육염의임상양상들을세 밀히조사해보아야한다. REFERENCES 1. Yunis EJ, Smamha FJ. Inclusion body myositis. Lab Invest 1971;25:240-248. 2. Badrising UA, Maat-Schieman M, van Duinen SG, Breedveld F, van Doorn P, van Engelen B, et al. Epidemiology of inclusion body myositis in the Netherlands: a nationwide study. Neurology 2000;55(9):1385-1387. 3. Needham M, Corbett A, Day T, Christiansen F, Fabian V, Mastaglia FL. Prevalence of sporadic inclusion body myositis and factors contributing to delayed diagnosis. J Clin Neurosci 2008;15(12):1350-1353. 4. Griggs RC, Askanas V, DiMauro S, Engel A, Karpati G, Mendell JR, et al. Inclusion body myostis and myopathies. Ann Neurol 1995;38:705-713. 5. Felice KJ, Relva GM, Conway SR. Further observations of on forearm flexor weakness in inclusion body myositis. Muscle Nerve 1998;21:659-661. 6. Houser SM, Calabrese LH, Strom M. Dysphagia in patients with inclusion body myositis. Laryngoscope 1998;108:1001-1005. 7. Schlesinger I, Soffer D, Lossos A, Meiner Z, Argov Z. Inclusion body myositis: atypical clinical presentations. Eur Neurol 1996; 36:89-93. 8. Limaye V, Scott G, Kwiatek R, Pile K. Inclusion body myositis associated with systemic lupus erythematousus (SLE). Aust N Z J Med 2000;30:275-276. 9. Kanellopoulos P, Baltoyiannis C, Tzioufas AG. Primary Sjogren s syndrome associated with inclusion body myositis. Rheumatology 2002;41:440-444. 10. Kim S, Genth E, Krieg T, Hunzelmann N. PM-Scl antibody positive systemic sclerosis associated with inclusion-body myositis. Rheumatology 2005;64:587-588. 11. Dalakas MC. Sporadic inclusioin body myositis-diagnosis, pathogenesis and therapeutic strategies. Nat Clin Pract Neurol 2006;2:437-447. 12. Dalakas MC. Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclusion body myositis. Curr Opin Neurol 2004;17:561-567. 13. Askanas V, Engel WK. Sporadic inclusion body myositis and its similarities to Alzhemier disease brain: recent approaches to diagnosis and pathogenesis, and relation to aging. Scand J Rheumatol 1998;27:389-405. 14. Pruitt JN 2 nd, Showalter CJ, Engel AG. Sporadic inclusion body myositis: counts of different types of abnormal fibers. Ann Neurol 1996;39:139-143. 15. Dalakas MC. The molecular and cellular pathology of inflammatory muscle disease. Curr Opin Pharmacol 2001;3:300-303. 16. Askanas V, Engel WK. Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer s and Parkinson s disease brains. Acta Neuropathol 2008;116:583-595. 17. Cupler EJ, Leon-Monzon M, Miller J, Semino-Mora C, Anderson TL, Dalakas MC. Inclusion body myositis in HIV-1 24 대한신경근육질환학회지 2010
and HTLV-1 infected patents. Brain 1996;119:1887-1893. 18. Ozden S, Gessain A, Gout O, Mikol J. Sporadic inclusion body myositis in a patent with human T-cell leukemia virus type 1 associated myelopathy. Clin Infect Dis 2001;32:510-514. 19. Needham M, Mastaglia FL. Sporadic inclusion body myositis: a continuing puzzle. Neuromuscul Disord 2008;18:6-16. 20. Dabby R, lange DJ, Trojaborg W, Hays AP, Lovelace RE, Brannagan TH, et al. Inclusion body myositis mimicking motor neuron disease. Arch Neurol 2001;58:1253-1256. 21. Lotz BP, Engel Ag, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis: observations in 40 patients. Brain 1989;112:727-747. 22. Phillips BA, Cala LA, Thickbroom GW, Melsom A, Zilko PJ, MAstaglia FL. Patterns of muscle involvement in sporadic inclusion body myositis. A clinical and MRI study. Muscle Nerve 2001;24:1526-1534. 23. Sekul EA, Chow C, Dalakas MC. Magnetic resonance imaging of the forearm as a diagnostic aid in patents with sporadic inclusion body myositis. Neurology 1997;48:863-866. 24. Schmidt J, Barthel K, Wrede A, Salajegheh M, Bähr M, Dalakas MC. Interrelation of inflammation and APP in sibm: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Brain 2008;131:1228-1240. 25. Choi YC, Kim TS, Kim SY. Increase in Transglutaminase 2 in Idiopathic Inflammatory. Eur Neurol 2004;51:10-14. 26. Choi YC, Park GT, Kim TS, Sunwoo IN, Steinert PM, Kim SY. Sporadic Inclusion Body Myositis Correlates With Increased Expression and Cross-linking by Transglutaminases 1 and 2. J Biol Chem 2000;275:8703-8710. 27. Badrising UA, Maat-Schieman M, van Duinen SG, Breedveld F, van Doorn P, van Engelen B, et al. Epidemiology of inclusion body myositis in the Netherlands: a nationwide study. Neurology 2000;66:1385-1387. 28. Hoogendijk JE, Amato AA, Lecky BR, Choy EH, Lundberg IE, Rose MR, et al. 119 th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands. Neuromuscul Disord 2004;14:337-345. 29. Chahin N, Engel AG. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Neurology 2008;70:418-424. 30. Oh SH, Kim SM, Sunwoo IN, Lee DH, Kim TS, Kim SH, et al. The Clinical and Pathological Characteristics of Polymyositis Using ENMC Diagnostic Criteria. J Korean Rheum Assoc 2008; 15:296-305. 31. Tawil R, Griggs RC. Inclusion body myositis. Curr Opin Rheumatol 2002;14:654-657. 32. Dahlbom K, Lindberg C, Oldfors A. Inclusion body myositis: morphological clues to correct diagnosis. Neuromuscul Disord 2002;12:853-857. 33. Hilton-Jones D, Miller A, Parton M, Holton J, Sewry C, Hanna MG. Inclusion body myositis: MRC Centre for Neuromuscular Diseases, IBM workshop, London, 13 June 2008. Neuromuscul Disord 2010;20:142-147. Korean Journal of Neuromuscular Disorders 2010 25