대한내과학회지 : 제 85 권제 3 호 2013 http://dx.doi.org/10.3904/kjm.2013.85.3.250 특집 (Special Review) - 척추관절병증 건선관절염의임상상과진단 연세대학교의과대학내과학교실류마티스내과 이상원 Clinical Manifestations and Diagnosis of Psoriatic Arthritis Sang-Won Lee Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Psoriatic arthritis (PsA) is an autoimmune arthritis related to psoriasis and one of seronegative spondyloarthropathies. PsA provokes joint pain and morning stiffness more than 30 minutes, which is relieved by exercise. PsA usually affects distal small joints and exhibits asymmetry, which is one of the typical characteristics of PsA and gives clues to make a differential diagnosis between PsA and rheumatoid arthritis. Thirty to forty patients with PsA experience arthritis in one large joint or asymmetric multiple joints. Arthritis in distal joints and arthritis mutilans often develop concurrently and patterns of PsA change along with disease progression. Spondylitis is observed in 20-30% of PsA patients. In contrast to ankylosing spondylitis, spondylitis in PsA present with mild clinical symptoms despite radiological progression, inflammation limited to one spinal tract, cervical spine dominance, non-marginal syndesmophytosis. Enthesitis is also one of the typical characteristics of PsA and it frequently affects Achilles tendon, plantar fascia and tendons inserting pelvic bones. Tenosynovitis can develop accompanied by enthesitis. Typical dactylitis (sausage digit), pitting edema and nail lesions, including nail pits, onycholysis, hyperkeratosis and splinter hemorrhage, also contribute to a differential diagnosis of PsA. Anterior uveitis, SAPHO syndrome, amyloidosis and IgA nephropathy are well-known extra-articular manifestation of PsA. In 2006, a new classification-criterion for PsA was suggested by the CASPAR study. The CASPAR criteria included 5 categories with a certain number of points; 1) skin psoriasis, 2) nail lesions, 3) dactylitis, 4) negative RF and 5) bone formation around joints. The CASPAR criteria should be applied to PsA patients having at least one of three (peripheral arthritis, spondylitis and enthesitis). (Korean J Med 2013;85:250-255) Keywords: Psoriatic arthritis; Clinical manifestation; Dignosis 서론건선관절염 (psoriatic arthritis) 는건선 (psoriasis) 과연관되어발생하는자가면역성 (autoimmune) 관절염이다. 대부분의 건선관절염환자에서류마티스인자 (rheumatoid factor) 가검출되지않는다는점과척추와말초관절을함께침범하는특징적인임상증상과경과로강직성척추염 (ankylosing spondylitis) 이나반응관절염 (reactive arthritis) 등과함께혈청음성척추 Correspondence to Sang-Won Lee, M.D. Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel: +82-2-2228-1984, Fax: +82-2-393-6884, E-mail: sangwonlee@yuhs.ac Copyright c 2013 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 250 - 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.
- Sang-Won Lee. Clinical manifestations and diagnosis of psoriatic arthritis - 관절염증 (seronegative spondyloarthropathy) 의하나로분류되어왔다 [1]. 건선관절염은 30에서 50대에주로호발하며남자와여자에서동일한비율로발생하고유병률은대략 1,000 명에서 1-2명정도이다 [2,3]. 건선관절염은지역과인종에따라서발생률의차이를보이는데, 백인의경우에는 6-42% 의건선환자에서건선관절염이발생하지만중국을제외한동양인의경우에는상대적으로낮은 1-9% 의환자에서건선관절염이발생하는것으로보고되었다 [4]. 약 30% 내외의건선관절염환자에서는피부에건선이발생하기전에관절염이먼저나타날수있는데, 이중절반의환자에서는관절염이발생한이후 1년이상의시간이지난다음에피부에건선이발생한다 [5]. 유사한임상증상과피부에건선이나타나기전에시작되는관절염등의이유로, 건선관절염은강직성척추염및반응관절염이나류마티스관절염 (rheumatoid arthritis) 과혼동될수있다. 따라서적절한치료를통한좋은예후를기대하기위해서는이들질환들과의감별진단이매우중요하다 [6]. 본소고에서는건선관절염의다양한임상증상과진단분류기준에대해서논하고자한다. 임상증상말초관절염 (peripheral arthritis) 건선관절염의증상은염증이발생한관절의통증과조조강직 (stiffness) 을특징으로하는데, 약 50% 이상의환자에서조조강직을경험하고대부분 30분이상지속되며쉬거나가만히있으면악화되고관절의운동을통해서완화되는양상을띤다. 압통 (tenderness) 과종창 (effusion) 이있는침범관절은비대칭적인분포를보이며주로는원위관절들 (distal joints) 을주로침범한다 [7]. 오랜시간동안관절염이지속되는경우, 침범관절에는심각한관절변형 (deformity) 이초래되는데, 특히원위관절에나타나는변형은 pencil-in-cup appearance 라는특징적인방사선학적소견을보이기도하는데, 이소견은침범관절을기준으로원위부뼈가연필모양으로파괴되어근위부뼈안에담긴모양에서비롯되었다. 비대칭적관절침범은 1973년 Moll과 Wright [8] 이건선관절염에서가장특징적인형태의관절소견으로강조한것이다. 비대칭적분포는주로대칭적인관절침범을특징으로하는류마티스관절염과구분되는중요한단서를제공하지만한편으로는질병초기에건선관절염이류마티스관절염에비해서소수의 관절침범을하기때문에비대칭적인관절침범을보일수있다는가설도있다 [9]. 건선관절염은모든환자에서사지말단의원위관절만침범하는것은아니다. 무릎관절과같은큰관절에도건선관절염이발생할수있는데, 30-40% 의환자에서발생할수있고대부분은중년이전의젊은나이에발생하며하나의관절침범이나비대칭적으로여러관절을침범하는형태로나타난다 [10]. 약 5% 의건선관절염환자에서는뼈의미란성 (erosive) 변화가진행되고파골 (bone-resorption) 현상의진행에따라서궁극적으로관절및주변뼈의파괴를초래하는단절성관절염 (arthritis mutilans) 이발생한다 [11]. 원위지절관절 (distal interphalangeal [DIP] joint) 를주로침범하는원위관절염이나단절성관절염은그자체로도건선관절염의특징적인관절염의형태이지만관절염의패턴은중복되는경우도있고시간이지남에따라서다른형태로바뀌기도한다. 이상의임상적특성으로인해서초기에는혈청음성류마티스관절염과혼동이되는경우가많지만원위관절염과비대칭적인관절침범이외에도척추관절병증이나지염 (dactylitis), 새로운뼈형성및특징적인피부건선병변은감별에도움을준다. 척추염 (spondylitis) 건선관절염에서척추염의발생은연구에따라서매우다양하다. 대략 20-30% 이상의환자에서발생하는것으로보고되고있으며건선관절염과동반된척추염은때때로강직성척추염과구분하기가어려운경우가있다 [12]. 하지만임상적으로강직성척추염에비해서요통 (back pain) 이나척추의운동장애 (limitation of motion, LOM) 등의증상이심하지않고한쪽의척수로 (spinal tract) 에국한되며말초관절염이잘동반한다는특징을보인다. 또방사선학적으로건선관절염은요추보다는경추침범이빈번하고비대칭적인천장관절염 (sacroiliitis), 비경계인대골극증 (non-marginal syndesmophytosis), 비대칭적인대골극증등은두질환의감별에도움을준다 [13]. 건선관절염과동반된척추염의전향적연구에따르면전체적으로인대골극증형성과천장관절염의발생빈도는시간이지남에따라서증가하는반면염증성목통증이나허리통증및강직, 천장관절의압통, 그리고척추의운동장애의빈도는증가하지않았다. 또다수의강직성척추염환자가가지고있는 HLA-B27 유전자는건선관절염의진행에영향 - 251 -
- 대한내과학회지 : 제 85 권제 3 호통권제 637 호 2013 - 을미치지않았다. 결론적으로건선관절염에의한척추염은방사선학적진행을보이기는하지만임상적으로심각한증상을유발하지않으며강직성척추염에비해서비교적좋은예후를갖는다 [13]. 골부착염 (enthesitis) 과건초염 (tenosynovitis) 골부착염은힘줄 (tendon) 이뼈에부착하는부위의염증을말한다. 골부착염은건선관절염의주요한임상적지표로서잘발생하는부위는아킬레스건 (Achilles tendon), 족저근막 (plantar fascia) 및골반뼈에부착하는힘줄들이다. 골부착염은보고에따라 10-60% 로다양하고임상적으로는골부착부위의심한통증과운동장애를특징으로하며골부착염은상지에비해서하지에더많이발생한다 [10]. 한연구에따르면아킬레스건염의경우증상이뚜렷하지않은건선관절염환자와건강인을근골격계초음파를이용하여검사를진행하였을때건선관절염환자에서더높은빈도로관찰되었다 [14]. 객관적으로골부착염을평가하기위해서여러 골부착염평가지표 (enthesitis assessment indexes) 가개발되었고현재임상적으로사용되는평가지표는아래와같다 ; Mander Enthesitis Index (66 sites); Major Enthesitis Index (12 sites); Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) (13 sites); Leeds Enthesitis Index (LEI) (6 site) [15-18]. 예로, LEI은좌 / 우측외측위관절융기 (lateral epicondyle), 좌 / 우측내측대퇴골관절융기 (medial femoral condyle), 좌 / 우측아킬레스건부착부위의 6 부위를 2점- 척도로평가하는지표로, 기술된여러지표중에서가장적은부위를포함하고있고활성도가높은건선관절염에서골부착염을평가하는데효과적인것으로입증되었다. 보통건초염은골부착염과함께존재하는데, 아킬레스건이외에호발하는부위로는손의굴근건 (flexor tendon), 척측수근신근 (extensor carpi ulnaris) 등이있다. 지염손가락이나발가락전체에미만성부종을특징으로하는지염은건선관절염의가장특징적인임상증상중하나로흔히 소시지가락 (sausage digit) 으로불린다. 지염은하나의손가락이나발가락에발생하기도하지만때로는여러부위에동시에발생하기도한다. 지염은종창과발적, 통증, 열감및관절의운동장애의임상적특징을갖는다. 보통은건선 관절염의급성기에발생하지만가끔은급성기이후의만성기에도통증을수반하지않은지염이관찰되기도한다. 지염은중수수지관절 (metacarpophalangeal joint) 과지절간관절 (interphalageal joint) 사이의연부조직의특징적인종창 (swelling) 으로정의되는데, 종창은굴근 (flexor muscle) 의염증과지절관관절의활막염의동반에기인하는것으로알려져있다 [19]. 이들구조는매우인접해있고지염의특성상전체적부종을특징으로하기에임상적으로수지굴근건염 (flexor tendinitis) 과지절관관절의활막염을구분하는것은매우어렵다. 지염은전체건선관절염환자의약 50% 에서발생하는것으로보고되었고임상적으로는지염이있는경우방사선학적관절손상의정도가심한반면항종양괴사인자 (tumor necrosis factor) 억제제에대한반응은좋은것으로알려져있다 [20,21]. 지염은건선관절염의특징적인임상증상이기는하지만다른질환에서도관찰될수있다. 만약지염을보이는환자가비대칭적소수관절염 (oligoarthritis) 과골부착염및요통을호소한다면반드시반응성관절염과의감별을요한다. 반응성관절염의피부병변은건선관절염과의감별진단의주된요소이며 HLA-B27 양성도감별에도움을준다. 손발톱병변 (nail lesions) 손발톱병변은건선관절염의또하나의특징적인임상증상이다. 손발톱병변에는손발톱오목 (nail pits), 손발톱박리 (onycholysis), 손발톱과다각화증 (nail hyperkeratosis) 과손발톱밑선상출혈 (splinter hemorrhage) 이있으며건선관절염환자의 80-90% 에서관찰된다 [22]. 손발톱오목은손발톱판 (nail plate) 세포이상에서기인되고손발톱판에경계가뚜렷하게함몰된부위를말하며날카로운도구로손발톱판을여러차례찌른것처럼보이기도한다. 손발톱박리는손발톱전체를침범할수도있고일부만침범할수도있는데곰팡이감염과감별을요한다. 피부건선은건선관절염의활성도와유의한상관관계를보이지않는것으로알려져왔으나건선관절염에의한손발톱병변의정도는피부건선과건선관절염의중등도와밀접한상관관계를보이는것으로알려져있다 [23]. 또한손발톱병변은건선환자에서높은관절염발생을시사한다. - 252 -
- 이상원. 건선관절염의임상상과진단 - 함요부종 (pitting edema) 건선관절염환자에서함요부종은주로상지와하지의말단에발생한다. 전체환자의약 20% 까지발생하는것으로보고되었으며, 이중 20% 의환자에서는함요부종이첫번째임상증상이었다 [24]. 함요부종은주로비대칭적으로하지에발생하며움직이거나누르면심한통증을호소한다. 임상적으로림프부종 (lymphedema) 이드물게건선관절염과동반하여발생하기도한다. 하지만림프부종에의한함요부종의경우에는주로힘줄의주행을따라서나타나며건초염이있는환자에서더잘관찰된다. 림프부종은통증이덜하고상지에호발하며대칭적인것이특징이다 [25]. 관절외임상증상건선관절염환자의약 2-25% 의환자는급성전방포도막염 (acute anterior uveitis) 을경험하게되는데, HLA-B27 을가진환자에서더빈번하다고보고되었다 [26]. 임상적경과는다른혈청음성척추관절병증과유사하다. 2-3% 의건선관절염환자는 SAPHO 증후군 (synovitis, acne, pustulosis, hyperostosis, osteitis) 을경험하는데, SAPHO 증후군환자의약 10% 는피부건선을경험하는것으로알려져있다 [27]. 이외에도드물기는하지만아밀로이도증 (amyloidosis), IgA 신증 (IgA nephropathy) 및대동맥질환등이동반될수있다 [28]. 진단기준 1971년 Moll과 Wright [8] 는건선관절염의정의를정리하기전까지는다양한정의가혼재되어사용되어왔다 : 1) 건선과연관되어서발생하는원위지절관절에국한된관절염, 2) 피부와관절이동시에호전과악화를반복하는건선과연관된관절염, 3) 조절이안되는만성건선에서발생된관절염, 4) 건선환자에서발생한심각한변형이초래된관절염, 5) 우연히병발된건선과류마티스관절염, 6) 비정형적 (atypical) 건선과동반된비정형적관절염, 7) 류마티스인자가음성인미란성다발관절염과동반된건선. Wright와 Moll [29] 은이러한다양한건선관절염의정의들은바탕으로하여 5개의 pattern으로분류하였다. 1) 원위지절관절을주로침범하는원위부관절염, 2) 5개이하의작은혹은큰관절을침범하는비대칭적소수관절염, 3) 류마티스관절염과유사한대칭적다발관절염, 4) 관절의변형과파괴를초래하는단절성관절염 (arthritis mutilans), 5) 천장관절과척추관절을포함한척추염. 다발관절염이차지하는비율이가장높으며그다음호발하는관절염은소수관절염이다. 원위지절관절을침범하는원위부관절염의빈도는약 20% 이며주로는척추염과동반되어나타난다. 척추염만발생하는경우는매우드물며보고에따라서약 2-4% 로알려져있다 [29]. 건선관절염에매우특이적인단절성관절염은다른 pattern과동반되어나타나는경우가많다 [30]. 이분류기준은심하지않은건선관절염을진단하기쉽지않다는점, 하나이상의 pattern을동시에가질수있다는점그리고추적관찰기간동안다른 pattern으로변할수있다는점등많은한계를지니고있지만단순한분류의장점으로오랫동안진료및임상시험에사용되어왔다 [31]. 하지만이후에진행된여러연구에서는모든환자를 Moll과 Wright에의한기준으로분류할수없음을알게되었고이에새로운진단기준에대한요구가있어왔다 [31,32]. 2006년기존의여러분류기준을통합하는새로운진단 Table 1. The classification criteria for psoriatic arthritis (the CASPAR criteria) ( > 3 points) [33] Category Points Skin psoriasis Current psoriasis 2 Personal history of psoriasis 1 Family history of psoriasis 1 Typical psoriatic nail dystrophy (onycholysis, pitting, hyperkeratosis) 1 Negative rheumatoid factor 1 Current dactylitis or history of dactylitis (recorded by a rheumatologist) 1 Hand or foot plain radiography: evidence of juxta articular new bone formation, appearing as ill defined ossification near joint margin (excluding osteophytes) 1-253 -
- The Korean Journal of Medicine: Vol. 85, No. 3, 2013 - 기준이 CASPAR (classification criteria for psoriatic arthritis) study group에의해서제시되었다 (Table 1). 이분류기준은 588명의건선관절염환자와 536명의타질환대조군의자료를분석하였는데, 대조군에는 384명의류마티스관절염, 72 명의강직성척추염, 38명의미분화성관절염 (undifferentiated arthritis), 28명의결체조직질환 (connective tissue disorder) 와 28명의기타질환환자가포함되었다 [33]. 민감도는 98.7%, 특이도는 91.4% 였으며캐나다와중국에서진행된 2개의다른연구에서이분류기준의유용성이검증되었다 [34,35]. 단이분류기준은반드시말초관절염, 척추병변또는골부착염등의염증성근골격계질환을가진환자에서만적용되어야한다. 중심단어 : 건선관절염 ; 임상상 ; 진단 REFERENCES 1. Gladman DD. Current concepts in psoriatic arthritis. Curr Opin Rheumatol 2002;14:361-366. 2. Shbeeb M, Uramoto KM, Gibson LE, O'Fallon WM, Gabriel SE. The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982-1991. J Rheumatol 2000;27:1247-1250. 3. Madland TM, Apalset EM, Johannessen AE, Rossebö B, Brun JG. Prevalence, disease manifestations, and treatment of psoriatic arthritis in Western Norway. J Rheumatol 2005; 32:1918-1922. 4. Tam LS, Leung YY, Li EK. Psoriatic arthritis in Asia. Rheumatology (Oxford) 2009;48:1473-1477. 5. Gladman DD, Shuckett R, Russell ML, Thorne JC, Schachter RK. Psoriatic arthritis (PSA): an analysis of 220 patients. Q J Med 1987;62:127-141. 6. Turkiewicz AM, Moreland LW. Psoriatic arthritis: current concepts on pathogenesis-oriented therapeutic options. Arthritis Rheum 2007;56:1051-1066. 7. Oriente P, Biondi-Oriente C, Scarpa R. Psoriatic arthritis. Clinical manifestations. Baillieres Clin Rheumatol 1994;8: 277-294. 8. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973;3:55-78. 9. Helliwell PS, Porter G, Taylor WJ; CASPAR Study Group. Polyarticular psoriatic arthritis is more like oligoarticular psoriatic arthritis, than rheumatoid arthritis. Ann Rheum Dis 2007;66:113-117. 10. Cantini F, Niccoli L, Nannini C, Kaloudi O, Bertoni M, Cassarà E. Psoriatic arthritis: a systematic review. Int J Rheum Dis 2010;13:300-317. 11. Helliwell PS. Established psoriatic arthritis: clinical aspects. J Rheumatol Suppl 2009;83:21-23. 12. Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM, Ballina Garcia J, Riestra Noriega JL, Lopez Larrea C. Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients. Br J Rheumatol 1991;30:245-250. 13. Hanly JG, Russell ML, Gladman DD. Psoriatic spondyloarthropathy: a long term prospective study. Ann Rheum Dis 1988;47:386-393. 14. De Simone C, Guerriero C, Giampetruzzi AR, Costantini M, Di Gregorio F, Amerio P. Achilles tendinitis in psoriasis: clinical and sonographic findings. J Am Acad Dermatol 2003;49:217-222. 15. Mander M, Simpson JM, McLellan A, Walker D, Goodacre JA, Dick WC. Studies with an enthesis index as a method of clinical assessment in ankylosing spondylitis. Ann Rheum Dis 1987;46:197-202. 16. Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al. Assessment of enthesitis in ankylosing spondylitis. Ann Rheum Dis 2003;62:127-132. 17. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187-1193. 18. Healy PJ, Helliwell PS. Measuring clinical enthesitis in psoriatic arthritis: assessment of existing measures and development of an instrument specific to psoriatic arthritis. Arthritis Rheum 2008;59:686-691. 19. Olivieri I, Salvarani C, Cantini F, et al. Fast spin echo-t2- weighted sequences with fat saturation in dactylitis of spondylarthritis: no evidence of entheseal involvement of the flexor digitorum tendons. Arthritis Rheum 2002;46: 2964-2967. 20. Brockbank JE, Stein M, Schentag CT, Gladman DD. Dactylitis in psoriatic arthritis: a marker for disease severity? Ann Rheum Dis 2005;64:188-190. 21. Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 2009;68:1387-1394. 22. Cassell SE, Bieber JD, Rich P, et al. The modified Nail Psoriasis Severity Index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis. J Rheumatol 2007;34:123-129. 23. Williamson L, Dalbeth N, Dockerty JL, Gee BC, Weatherall R, Wordsworth BP. Extended report: nail disease in psoriatic arthritis: clinically important, potentially treatable and often overlooked. Rheumatology (Oxford) 2004;43:790-794. 24. Olivieri I, Brandi G, Padula A, et al. Lack of association - 254 -
- Sang-Won Lee. Clinical manifestations and diagnosis of psoriatic arthritis - with spondyloarthritis and HLA-B27 in Italian patients with Whipple's disease. J Rheumatol 2001;28:1294-1297. 25. Salvarani C, Cantini F, Olivieri I, et al. Distal extremity swelling with pitting edema in psoriatic arthritis: evidence of 2 pathological mechanisms. J Rheumatol 1999;26: 1831-1834. 26. Queiro-Silva R, Torre-Alonso JC, Tinturé-Eguren T, López- Lagunas I. The effect of HLA-DR antigens on the susceptibility to, and clinical expression of psoriatic arthritis. Scand J Rheumatol 2004;33:318-322. 27. Dumolard A, Gaudin P, Juvin R, Bost M, Peoc'h M, Phelip X. SAPHO syndrome or psoriatic arthritis? a familial case study. Rheumatology (Oxford) 1999;38:463-467. 28. Wong K, Gladman DD, Husted J, Long JA, Farewell VT. Mortality studies in psoriatic arthritis: results from a single outpatient clinic: I. causes and risk of death. Arthritis Rheum 1997;40:1868-1872. 29. Wright V, Moll JM. Psoriatic arthritis. Bull Rheum Dis 1971;21:627-632. 30. Haddad A, Chandran V. Arthritis mutilans. Curr Rheumatol Rep 2013;15:321. 31. Jones SM, Armas JB, Cohen MG, Lovell CR, Evison G, McHugh NJ. Psoriatic arthritis: outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33:834-839. 32. McHugh NJ, Balachrishnan C, Jones SM. Progression of peripheral joint disease in psoriatic arthritis: a 5-yr prospective study. Rheumatology (Oxford) 2003;42:778-783. 33. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:2665-2673. 34. Chandran V, Schentag CT, Gladman DD. Sensitivity and specificity of the CASPAR criteria for psoriatic arthritis in a family medicine clinic setting. J Rheumatol 2008;35:2069-2070. 35. Leung YY, Tam LS, Ho KW. Evaluation of the CASPAR criteria for psoriatic arthritis in the Chinese population. Rheumatology (Oxford) 2010;49:112-115. - 255 -