대한내과학회지 : 제 87 권제 1 호 2014 http://dx.doi.org/10.3904/kjm.2014.87.1.34 의학강좌 - 개원의를위한모범처방 (Current Clinical Practice) 류마티스다발근통의진단과치료 울산대학교의과대학서울아산병원류마티스내과 홍석찬 김용길 Diagnosis and Treatment of Polymyalgia Rheumatica Seokchan Hong and Yong-Gil Kim Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Polymyalgia rheumatica (PMR) is a chronic inflammatory disorder that usually affects adults over 50 years of age. It is characterized by pain and stiffness of the neck, shoulders and hips. Laboratory tests have shown marked elevation of acute phase reactants (ESR and CRP), but there is no specific test to diagnose PMR. Recently, the European League Against Rheumatism and the American College of Rheumatology jointly proposed a new set of classification criteria for PMR. The mainstay of PMR treatment is low-dose glucocorticoids (prednisolone 10-20 mg/day). patients with PMR usually respond very well to steroid therapy within a few days to one week, but will often relapse despite treatment. (Korean J Med 2014;87:34-38) Keywords: Polymyalgia rheumatica; Criteria; Treatment 서론류마티스다발근통은양측어깨및고관절의통증과경직을특징으로하는만성염증성류마티스질환으로주로 50 세이상의고령에서발생한다. 류마티스다발근통의진단에는특징적인진단적검사가존재하지않으므로다양한임상적인소견에근거하여진단을내리게된다. 이질환은고령에서다발성으로발생할수있는근육혹은관절통증의주요감별질환중하나로저용량의부신피질호르몬에잘반응하는질환이다. 본종설에서는최근에제안된류마티스다발근통의새로운분류기준및치료를소개함으로써류마티 스질환을전공하지않은일선개원의의진료에도움이되고자한다. 역학및병인류마티스다발근통은대개 50세이상의고령에서발생하며평균호발연령은약 75세로 70세에서 80세사이에가장많이발생하는것으로알려져있다. 미국에서수행된연구에따르면 50세에서 59세의발병률은십만명당약 20명이나 70세에서 79세의경우십만명당 112명으로급격히증가되었다 [1]. 진단기준에따라차이가있으나 50세이상혹은 65세 Correspondence to Yong-Gil Kim, M.D., Ph.D. Division of Rheumatology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olymphic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-3279, Fax: +82-2-3010-6969, E-mail: bestmd2000@amc.seoul.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 34 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Seokchan Hong, et al. Diagnosis and treatment of polymyalgia rheumatica - 이상의연령을진단기준에포함시킬정도로높은연령은진단및감별에중요한인자로고려되고있다. 성별에따른발병률은류마티스관절염과유사하게여성이남성보다 2-3 배높은것으로보고되고있다 [2]. 류마티스다발근통의발병원인은잘알려져있지않으며유전적요인과환경적요인등의복합적인인자에의해유발되는것으로생각하고있다. Parvovirus B19이나 Mycoplasma pneumoniae 등과의관련성을시사하는역학연구등이있으나실제특정감염증과류마티스다발근통의발병을직접적으로증명한연구는없다 [3]. 계절에따른발병빈도의차이를보이며대체적으로겨울보다는여름에호발한다는결과가있으나상반되는결과도있어단정적으로이야기하기어렵다 [4,5]. 유전학적요인으로는 HLA-DRB1의특정유전형과질병의감수성증가에대한보고가있으며이외에도 intercellular adhesion molecule 1, interleukin-1 receptor antagonist, interleukin-18 등의유전적다형태 (polymorphism) 와의관련성도보고되고있다 [6-8]. 현재까지의연구결과를종합하면류마티스다발근통은특정유전적혹은환경적요인에의한발병보다는이들의다양한상호작용에의해발병하는것으로추정된다. 려울수있다 [10]. 이학적검사에서양쪽어깨관절의능동적움직임제한 (limitation of active motion) 이나타나며통증이심할경우수동적움직임에도제한이있을수있다. 근력은대개의경우보존되어있으므로근력의저하가보이는경우근육염 (myositis) 에대한감별이필요할수있다. 우리나라에는드문것으로되어있으나두통, 측두부를비롯한두피부위압통 (scalp tenderness) 및비후, 시력저하등의증상이있을경우거대세포동맥염 (giant cell arteritis) 가능성도감별해야한다. 검사실검사에서는적혈구침강속도 (erythrocyte sedimentation rate, ESR) 및 C-반응단백질 (C-reactive protein, CRP) 의뚜렷한증가가관찰된다. 대부분의환자에서 40 mm/hr 이상의적혈구침강속도증가가관찰되며약 20% 의환자에서는 100 mm/hr 이상의두드러진증가가관찰된다. 또한빈혈이나알부민의감소와같은염증반응으로인한비특이적인검사소견이동반될수있으나학행항체 (anti-nuclear antibodies) 와류마티스인자 (rheumatoid factor), 항CCP항체 (anti-ccp antibodies) 등과같은자가항체는대부분음성이다. 심한근육통과달리근육효소수치, 근전도검사및근육조직검사등은정상소견을보인다. 임상증상 진 단 류마티스다발근통은어깨및고관절, 경부의통증과경직을특징으로한다. 대개급성혹은아급성으로발병하게되며어깨관절침범이 70-95% 로가장흔하며엉덩이및경부침범은 50-70% 정도로알려져있다. 전신적인증상으로피로감, 미열, 체중감소등이약절반의환자에서동반될수있다. 양측성의경부, 어깨및골반이음구조 (pelvic girdle) 의통증과더불어 30분이상지속되는조조강직이약 1개월이상지속될때류마티스다발근통을의심할수있으며근위부근육및관절을주로침범하는것이특징이다. 이환된부위는움직임에의해악화될수있으며대개의경우일상적인활동에제약을가져온다. 약절반의환자에서는원위부근골격계증상을동반할수있으며이경우손목굴증후군 (carpal tunnel syndrome) 및손목, 손과같은말초관절의부종및통증으로나타난다 [9]. 드물게근위부의특징적인증상없이말초관절염형태로만나타날수있으므로이경우류마티스관절염을비롯한다른염증성관절염과의감별이어 류마티스다발근통은특징적인실험실검사및병리학적소견이없으므로임상증상을기반으로진단하게된다. 그동안다양한진단기준이제시되어왔으며대부분고령에서의양측성어깨통증과같은특징적인임상증상과적혈구침강속도의증가등을진단을위한기준으로제시하였다. 이외에도저용량 (prednisolone 20 mg/day 이하 ) 글루코코르티코이드 (glucocorticoid) 에대한신속하고뚜렷한증상의호전등을포함시키기도하였다. 하지만최근까지도류마티스다발근통의진단에대한표준화된기준이부재하였고, 이로인해그동안병인의이해및새로운치료의개발과같은여러부분에서어려움을겪어온것이사실이다. 이에따라그간의연구결과를바탕으로 2012년유럽및미국류마티스학회에서류마티스다발근통의진단을위한새로운분류기준을제시하였다 [11]. 제시된분류기준은 50세이상에서 12주이내새롭게발병된양측성어깨통증및비정상적급성염증반응의상승을가지는환자를대상으로적용하게되어있으며 - 35 -
- 대한내과학회지 : 제 87 권제 1 호통권제 647 호 2014 - Table 1. Polymyalgia rheumatica classification criteria scoring algorithm a Points without US (0-6) Points with US (0-8) b Morning stiffness duration > 45 min 2 2 Hip pain or limited range of motion 1 1 Absence of RF or ACPA 2 2 Absence of other joint involvement 1 1 At least 1 shoulder with subdeltoid bursitis and/or biceps tenosynovitis and/or glenohumeral synovitis (either posterior or axillary) and at least 1 hip with synovitis and/or trochanteric bursitis NA 1 Both shoulders with subdeltoid bursitis, biceps tenosynovitis, or glenohumeralsynovitis NA 1 Required criteria: age 50 years, bilateral shoulder aching, and abnormal CRP and/or ESR. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor; ACPA, anti-citrullinated protein antibody; NA, not applicable. a A score of 4 or more is categorized as polymyalgia rheumatica (PMR) in the algorithm without ultrasound (US) and a score of 5 or more is categorized as PMR in the algorithm with US. b Optional ultrasound criteria. Table 2. Differential diagnosis of polymyalgia rheumatica Rheumatological diseases Rheumatoid arthritis Spondyloarthritis Crystal induced arthritis (eg. calcium pyrophosphate disease) Remitting seronegative symmetric synovitis with pitting edema syndrome Vasculitis (giant cell arteritis, ANCA-associated vasculitis) Inflammatory myopathies (dermatomyositis, polymyositis) Non-inflammatory musculoskeletal disorders Rotator-cuff disease Adhesive capsulitis Degenerative joint disease Fibromyalgia Infections Viral Bacterial sepsis, endocarditis, disc space infection, septic arthritis Mycobacterial (eg, tuberculosis) Malignant diseases Solid, haematological Miscellaneous disorders Depression Drug-induced myopathy (eg, statins) 조조강직및고관절통증, 운동제한등으로이루어진여러항목의점수화된체계를제시하고있다 (Table 1). 최근활발 히연구가진행되고있는초음파소견을바탕으로별도의점수체계를따로제시하고있는것이이전의진단기준과다른흥미로운특징이다. 영상학적검사중단순방사선촬영은대부분정상소견으로진단에큰도움이되진않지만다른질병을감별하기위해시행할수있다. 최근류마티스다발근통진단시초음파이용에관한연구가활발히진행되어왔고진단의특이도를향상시키는것으로알려져 2012년새롭게제시된분류기준가운데주요한영상검사소견으로포함되었다. 류마티스다발근통에서발견되는초음파소견은주로관절주변조직의이상소견이며어깨관절의경우삼각근하 (subdeltoid), 견봉하 (subacromial) 낭염 (bursitis) 및이두근건초염 (biceps tenosynovitis) 이보일수있는것으로되어있다. 이외에도고관절의활막염소견도동반될수있다. 하지만이러한초음파검사의이상소견은여타의다른염증성관절염에서도관찰될수있는비특이적인소견이므로류마티스다발근통이임상적으로의심되는환자에서선택적으로시행하여야진단에도움을받을수있다. MRI 검사상양측성삼각근하 (subdeltoid), 견봉하 (subacromial) 낭염 (bursitis) 과같은이상소견이관찰될수있으나역시질병특이적인소견은아니다. PET의경우류마티스다발근통환자에서일반적으로시행되지는않으나악성종양이나대혈관염등과의감별이어려운경우도움을받을수있다. 류마티스다발근통은 ESR/CRP 상승외에는특징적인검 - 36 -
- 홍석찬외 1 인. 류마티스다발근통의진단과치료 - 사실, 영상학적혹은병리학적소견이없기때문에비특이적근육통을호소할수있는여러가지다양한질병을감별하는것이무엇보다도중요하다 (Table 2). 최근연구에따르면류마티스다발근통을진단받은환자에서 6개월내악성종양의발현빈도가정상인에비해약 1.7배증가한보고가있다 [12]. 즉, 류마티스관절염을비롯한만성염증성관절염뿐만아니라악성종양에서동반되는비특이적증상을류마티스다발근통으로오인할수있으므로주의하여야한다. 치료표준치료는저용량글루코코르티코이드로서약물투여후수일내신속하고뚜렷한증상의호전을보이므로이러한특징은류마티스다발근통의진단기준중하나로제시되고있다 [13]. 일반적으로초기치료는저용량 (prednisolone 15-20 mg/day) 글루코코르티코이드투여로충분하며 ESR 등과같은검사실검사소견과더불어임상증상도대부분함께호전된다. 저용량글루코코르티코이드투여에반응을보이는경우대개 2-4주정도는초기치료용량을유지하게되며이후용량을서서히감량할것을추천한다. 글루코코르티코이드감량방법에대한체계적인연구는없으나최근수행된메타분석에따르면 prednisolone 10 mg/day 이하투여용량의경우 1 mg/month 미만으로서서히감량하는것이향후재발위험도를낮출수있음을보고하였다 [14]. 그러므로글루코코르티코이드는투여는대부분 1-2년이상장기간투여하게되고이에따른당뇨및골다공증등과같은부작용발생에대한특별한주의가필요하다 [15,16]. 하지만비스테로이드소염제 (NSAID) 의투여는일반적으로큰도움을주지못하는것으로알려져있다. 메토트렉세이트 (methotrexate) 를비롯한면역억제제투여를통해글루코코르티코이드대체효과를기대하는연구가있어왔다. 무작위이중맹검연구에따르면메토트렉세이트의병용투여가글루코코르티코이드투여의누적용량및재발의빈도를줄일수있었다고보고하였으나 [17] 이후동일연구의 5년장기간추적관찰결과그차이는소실되었다 [18]. 또다른연구에서도메토트렉세이트투여에따른글루코코르티코이드보존효과 (sparing effect) 는관찰할수없었다 [19]. 따라서현재모든류마티스다발근통환자에서메토트렉세이트의투여가권장되지는않으며재발을경험한환자혹은 글루코코르티코이드투여에따른부작용의위험도가높은환자등에서선별적으로투여를고려할수있겠다 [2]. 최근류마티스관절염치료제로일차항류마티스제제에반응이충분하지않은경우이차치료제로사용할수있는여러생물학적제제에대한연구가류마티스다발근통에서도많은관심을갖고진행되고있다. 우선종양괴사인자억제제 (tumor necrosis factor inhibitor) 의투여를통해류마티스다발근통재발의빈도혹은글루코코르티코이드중단에미치는영향을보고자시행한무작위대조시험연구에서아쉽게도종양괴사인자억제제투여효과를관찰할수없었다 [20]. 최근에인터루킨-6 수용체억제제인 tocilizumab 의단독투여로류마티스다발근통이효과적으로치료되었음을보고한연구가있으나이에대해서는향후좀더많은연구가필요할것으로보인다 [21]. 예후류마티스다발근통은재발이비교적흔한질병으로치료를지속함에도약 50% 에서재발을경험하는것으로알려져있으며, 글루코코르티코이드의빠른감량, 여성혹은 CRP의지속상승등이재발과관련된요인으로알려져있다 [15,22]. 따라서규칙적인 ESR/CRP 측정및임상증상의평가가질병의재발을감시하기위해필요하다. 일부환자에서는만성재발성경과를보여수년간글루코코르티코이드투여가필요한경우도있다 [23,24]. 이경우글루코코르티코이드장기간투여에따른심혈관질환발생과같은타질병의이환가능성에대한고려와관심이장기적으로필요하겠다. 요약류마티스다발근통은고령에서발생하는만성염증성류마티스질환으로급성으로발생한어깨및고관절의통증과경직증상을호소하는환자에서의심할수있다. 류마티스다발근통의진단을위한특징적인실험실혹은방사선적검사가없으므로다양한임상소견에근거하여진단을내리게되며다발성근육통증을호소할수있는다양한질병을감별하는것이중요하다. 저용량글루코코르티코이드가표준치료로서치료에신속하고뚜렷한반응을보이지만재발이비교적흔한만성염증성질환이다. 최근에는류마티스다발근 - 37 -
- The Korean Journal of Medicine: Vol. 87, No. 1, 2014 - 통의분류기준이새롭게제시되었으며만성재발성환자에서생물학적제제의투여에대한연구가활발히진행되고있다. 중심단어 : 류마티스다발근통 ; 분류기준 ; 치료 REFERENCES 1. Chuang TY, Hunder GG, Ilstrup DM, Kurland LT. Polymyalgia rheumatica: a 10-year epidemiologic and clinical study. Ann Intern Med 1982;97:672-680. 2. Kermani TA, Warrington KJ. Polymyalgia rheumatica. Lancet 2013;381:63-72. 3. Elling P, Olsson AT, Elling H. Synchronous variations of the incidence of temporal arteritis and polymyalgia rheumatica in different regions of Denmark; association with epidemics of Mycoplasma pneumoniae infection. J Rheumatol 1996; 23:112-119. 4. Smeeth L, Cook C, Hall AJ. Incidence of diagnosed polymyalgia rheumatica and temporal arteritis in the United Kingdom, 1990-2001. Ann Rheum Dis 2006;65:1093-1098. 5. Perfetto F, Moggi-Pignone A, Becucci A, et al. Seasonal pattern in the onset of polymyalgia rheumatica. Ann Rheum Dis 2005;64:1662-1663. 6. Weyand CM, Hunder NN, Hicok KC, Hunder GG, Goronzy JJ. HLA-DRB1 alleles in polymyalgia rheumatica, giant cell arteritis, and rheumatoid arthritis. Arthritis Rheum 1994;37: 514-520. 7. Cid MC, Ercilla G, Vilaseca J, et al. Polymyalgia rheumatica: a syndrome associated with HLA-DR4 antigen. Arthritis Rheum 1988;31:678-682. 8. González-Gay MA, Amoli MM, Garcia-Porrua C, Ollier WE. Genetic markers of disease susceptibility and severity in giant cell arteritis and polymyalgia rheumatica. Semin Arthritis Rheum 2003;33:38-48. 9. Salvarani C, Cantini F, Macchioni P, et al. Distal musculoskeletal manifestations in polymyalgia rheumatica: a prospective followup study. Arthritis Rheum 1998;41:1221-1226. 10. Caporali R, Montecucco C, Epis O, Bobbio-Pallavicini F, Maio T, Cimmino MA. Presenting features of polymyalgia rheumatica (PMR) and rheumatoid arthritis with PMR-like onset: a prospective study. Ann Rheum Dis 2001;60:1021-1024. 11. Dasgupta B, Cimmino MA, Kremers HM, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum 2012;64:943-954. 12. Muller S, Hider SL, Belcher J, Helliwell T, Mallen CD. Is cancer associated with polymyalgia rheumatica? a cohort study in the General Practice Research Database. Ann Rheum Dis 2013. doi: 10.1136/annrheumdis-2013-203465. 13. Healey LA. Long-term follow-up of polymyalgia rheumatica: evidence for synovitis. Semin Arthritis Rheum 1984;13: 322-328. 14. Hernández-Rodríguez J, Cid MC, López-Soto A, Espigol- Frigolé G, Bosch X. Treatment of polymyalgia rheumatica: a systematic review. Arch Intern Med 2009;169:1839-1850. 15. Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR, Hunder GG, Gabriel SE. Relapse in a population based cohort of patients with polymyalgia rheumatica. J Rheumatol 2005;32:65-73. 16. Gabriel SE, Sunku J, Salvarani C, O'Fallon WM, Hunder GG. Adverse outcomes of antiinflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum 1997;40:1873-1878. 17. Caporali R, Cimmino MA, Ferraccioli G, et al. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2004;141:493-500. 18. Cimmino MA, Salvarani C, Macchioni P, et al. Long-term follow-up of polymyalgia rheumatica patients treated with methotrexate and steroids. Clin Exp Rheumatol 2008;26: 395-400. 19. Van der Veen MJ, Dinant HJ, van Booma-Frankfort C, van Albada-Kuipers GA, Bijlsma JW. Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis? Ann Rheum Dis 1996; 55:218-223. 20. Salvarani C, Macchioni P, Manzini C, et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med 2007;146:631-639. 21. Macchioni P, Boiardi L, Catanoso M, et al. Tocilizumab for polymyalgia rheumatica: report of two cases and review of the literature. Semin Arthritis Rheum 2013;43:113-118. 22. Salvarani C, Cantini F, Niccoli L, et al. Acute-phase reactants and the risk of relapse/recurrence in polymyalgia rheumatica: a prospective followup study. Arthritis Rheum 2005;53:33-38. 23. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 2002; 347:261-271. 24. Ayoub WT, Franklin CM, Torretti D. Polymyalgia rheumatica: duration of therapy and long-term outcome. Am J Med 1985;79:309-315. - 38 -