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1 대한내과학회지 : 제 87 권제 4 호 특집 (Special Review) - 류마티스질환의새로운진단기준 전신홍반루푸스의새로운분류기준 건국대학교의학전문대학원내과학교실 이상헌 The New Classification Criteria of Systemic Lupus Erythematosus Sang-Heon Lee Division of Rheumatology, Department of Internal Medicine, Konkuk Universtiy School of Medicine, Seoul, Korea Systemic lupus erythematosus (SLE) is a prototype for multi-system, autoimmune diseases of unknown etiology, characterized by the production of autoantibodies. SLE can involve any organ system of the body with constitutional symptoms, including musculoskeletal, skin, renal, neuropsychiatric, cardiovascular, respiratory and gastrointestinal systems. These wide spectra of disease manifestations have made disease classification difficult. American College of Rheumatology (ACR) proposed classification criteria for SLE for research purpose in 1982, which had been widely used for research purpose and not for diagnosis. In 1997, these criteria were updated with further recognition of antiphospholipid antibodies, but not validated. But ACR criteria didn't still meet the necessity for earlier diagnosis of SLE. In order to improve clinical relevance and incorporate new knowledge to the field of lupus immunology, the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC), an international lupus expert group dedicated to clinical research on lupus, revised the ACR systemic lupus classification criteria in The new 2012 SLICC criteria were validated using a large set of patient scenarios rated by experts. The history and diagnostic utility of SLE criteria are covered in this review. (Korean J Med 2014;87: ) Keywords: Systemic lupus erythematosis; Diagnosis 서론전신성홍반루푸스 (systemic lupus erythematosus, SLE) 는전신을침범하는대표적자가면역질환으로자가항체형성을특징으로하며피부, 신장, 신경계, 근골격계, 심혈관, 폐, 조혈기관등에다양한임상증상을나타낸다. SLE는장기특이자가면역질환과는달리발병시에도환자개개인마다다양 한증상으로나타나며질병경과에따라나타나는임상증상과소견도다양하다 [1]. 특히자가항체가환자의혈청에서대부분발견되지만항핵항체의경우다른자가면역질환에서도나타나특이도가떨어지며, 질환특이항체로알려진항dsDNA 항체, 항Sm항체등은모든환자에서나타나지는않고, 항체역가도질병활성도에따라달리나타나민감도는떨어지는단점이있다. Correspondence to Sang-Heon Lee. M.D., Ph.D. Division of Rheumatology, Department of Internal Medicine, Konkuk University Medical Center, Neungdong-ro, Gwangjin-gu. Seoul , Korea Tel: , Fax: , shlee@kuh.ac.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 Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 87, No. 4, SLE 진단기준으로가장널리이용된것은 1982년미국류마티스학회 (American College of Rheumatology, ACR) 에서제시된분류기준이있다 [2]. 이후 1997년에일부개정이이루어져현재거의사용되지않는매독반응위양성반응이삭제되고, 대신항인지질항체검사 ( 항cardiolipin항체, lupus anticoagulant) 로추가대체된것이특징이다 [3]. 그러나이런분류기준은의학자들사이에임상연구수행을위한분류기준일뿐, 진단적기준으로사용하기에는문제점이노출되었다. 그러나이런분류기준에해당하는항목이 SLE의모든임상양상이나실험실결과를반영하고있는것은아니기때문에 SLE가강력히의심되지만분류기준을만족시키지못하는경우가있다. 예를들어항핵항체가양성이고, 신장조직검사에서루푸스신염에합당한소견이있는경우 SLE 진단이될수있지만 1997년진단기준에따르면 2개밖에충족하지않으므로이분류기준에들어가지못하는모순점이있다. 이런점을개선하기위해루푸스전문가그룹으로이루어진 Systemic Lupus International Collaborating Clinic (SLICC) 에서 2012년새로운분류기준을제안하였다. 이기준에서는크게다양한면역학적검사이상에근거한면역학적기준과전신적임상소견에근거한임상기준의크게두가지로분류하였고, 신장조직검사로확진된루푸스신염에가중치를둔것이특징이다 [4]. 새로운진단기준은 1997년 ACR 기준에비해민감도를높이고, 이전에 SLE로분류되지못했던환자들이비교적초기부터진단되어치료와적절한관리가시행될수있을것으로기대된다. 본론 1982 년미국류마티스학회분류기준지난수십년간교과서를비롯하여관찰연구, 임상연구에는 1982년 ACR SLE 분류기준을사용하였다 [2]. 그이전에는 1971년 SLE 예비분류기준이사용되었으나 [5] 이후에표준혈청학적검사로사용되는자가항체검사 ( 항핵항체, 항DNA 항체 ) 등이개정되지않아새로운진단기준의필요성이제기되었고, 미국류마티스학회내진단및치료기준소위원회가구성되어 Tan 등이주축이되어 1982년 SLE 분류기준이제정되었다 (Table 1). 첫 4개항목은피부항목에관한것으로광과민성, 구강궤양, 뺨발진, 원판상홍반으로구성되었다. 다음 4개항목은특정기관침범과관련된것으로심장 이나폐, 신장, 중추신경계, 관절침범에대한내용을포함한다. 나머지 3개기준은혈액검사로빈혈, 백혈구감소증, 혈소판감소증, 항핵항체양성, LE세포양성, SLE 특이항체로알려진항DNA항체, 항Sm항체, 매독위양성반응등이포함되었다. 위와같은 11개기준중에서 4개이상을충족시키면 SLE로진단할수있다. 이런항목들은모두동시에존재해야하는것은아니며관찰시기동안에단계적으로나타난경우도포함된다. 예를들어관절염이나혈소판감소증과같은항목이몇개월에걸쳐나타나다가수개월혹은수년후에항핵항체양성반응, 특징적뺨발진등이나타나면진단기준에부합하게된다. 본분류기준은총 18개기관에서 SLE 전문가에의해수집된 177명의환자와 162명의대조군 ( 나이, 성별, 인종유사한비외상성, 비퇴행성결체조직질환 ) 으로구성되어검증되었다. 이들환자의정보를 ARAMIS (American Rheumatism Association Medical Information System) 라는컴퓨터데이터베이스에저장되어분석되었고이분류기준을이용할경우민감도 96%, 특이도 96% 를나타내어이후 SLE 연구에서표준분류기준으로사용되었다 [2]. 그러나이러한분류기준으로연구목적으로제정되어실제로임상에서환자를진단하는데문제점이있고, 단지임상적, 혈청학적, 병태생리적연구를진행하는데기준이되는척도로이용되었다 년미국류마티스학회개정판 1982년제정된 SLE 분류기준은이후 10년이상표준으로사용되었으나이후개발되고검증된새로운자가항체검사법이확립되어새로운개정의필요성이제기되었다. 15년후 1997년개정된분류기준의특징은말초혈액도말에서관찰하던 LE세포검사가삭제되고, 대신항인지질항체검사로대체된것이특징이다 (Table 1). LE세포검사는항핵항체검사가 SLE의표준선별검사로확립된이후에는대부분검사실에서더이상측정하지않고있는현실을반영하였다. 또한 LE세포검사가민감도및객관성면에서항핵항체검사에비해현저히떨어지고 ( 민감도 : LE세포검사 73% vs 항핵항체 96%), 검사시간도오래소요되어현재는일부체액에서 SLE로인한원인을감별하는용도외에는거의사용되지않는현실을반영하였다. 1997년개정판의핵심은면역검사항목에대한변화로항인지질항체에대한검사방법이확립되면서항cardiolipin항체, lupus anticoagulant검사양성이추

3 - Sang-Heon Lee. The New Classification Criteria of SLE - Table versus 1997 revised criteria for the classification of systemic lupus erythematous [2,3] Criterion Definition Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds 2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions 3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician 5. Arthritis Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion 6. Serositis 1. Pleuritis convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion 2. Pericarditis documented by electrocardigram or rub or evidence of pericardial effusion 7. Renal disorder 1. Persistent proteinuria > 0.5 grams per day or > than 3+ if quantitation not performed 2. Cellular casts may be red cell, hemoglobin, granular, tubular, or mixed 8. Neurological disorder 1. Seizures in the absence of offending drugs or known metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance 2. Psychosis in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic disorder 1. Hemolytic anemia with reticulocytosis 2. Leukopenia < 4,000/mm 3 on 2 occasions 3. Lymphopenia < 1,500/mm 3 on 2 occasions 4. Thrombocytopenia < 100,000/mm 3 in the absence of offending drugs 10. Immunologic disorder 1. Positive LE cell preparation 1. Anti-DNA: antibody to native DNA in abnormal titer 2. Anti-DNA: antibody to native DNA in abnormal 2. Anti-Sm: presence of antibody to Sm nuclear antigen titer 3. Positive finding of antiphospholipid antibodies on: 3. Anti-Sm: presence of antibody to Sm nuclear 1) An abnormal serum level of IgG or IgM anticardiolipin antibodies, antigen 4. False-positive serologic test for syphilis known 2) A positive test result for lupus anticoagulant using a to be positive at least 6 months and confirmed standard method, or by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test firmed by Treponema pallidum immobilization or 3) A false-positive test result for at least 6 months con- fluorescent treponemal antibody absorption test 11. Antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs The classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person is defined as having SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation. 가된점이다 [6] 년면역학적이상항목에포함된매독반응위양성반응의원인이대부분항인지질항체에의한것이밝혀지면서이에대한표준검사법이추가되었고, 다만아직검사가어려운지역도있어매독반응위양성반응은이전과같이포함된것이특징이다. 항인지질항체항목이추가되면서과거미분류결체조직질환 (undifferentiated connective tissue disease) 혹은항인지질항체증후군환자군이새로운진단기준으로포함될가능성이높아져 SLE 발병률, 유병률변화에도영향을미쳤다 [7]. SLE 의사망률은과거에는질환에의한장기손상 ( 신장, 뇌신경, 심폐질환등 ) 이영향을미쳤으나면역억제제의사용으로많이감소하였고, 점차적으로 SLE자체보다는심혈관계질환이주된사망원인

4 - 대한내과학회지 : 제 87 권제 4 호통권제 650 호 으로제기되고있다. 이런면에서혈전증과관련있는항인지질항체검사의진단항목추가는 SLE 환자에서항혈전치료에관심을갖는계기가되었다 [8]. 다만당시에는항인지질항체및 lupus anticoagulant 검사법이기관마다달라이에대한표준화된검사법으로해석해야한다는의견이지적되었다. 항핵항체검사는민감도는매우높지만 (96-98%), 특이도는상대적으로낮은편으로 (49-72%) SLE 진단에서선별검사로서가치가높다. 즉항핵항체는질병경과중에거의모든환자에서양성이나오기때문에항핵항체검사를반복해서시행했을때모두음성이고다른자가항체가음성이라면 SLE가아닐가능성이높다. 반면고역가의항DNA항체나항 Sm 항체는 SLE특이항체이므로합당한임상양상이있다면 SLE진단이가능하다 [9]. 따라서 1997년진단기준에서가장핵심적인부분은면역학적이상과항핵항체에대한항목이다. 이는이후에언급할새로운분류기준에서면역학적기준과임상기준을나누는근거가되었다. 1997년기준에따르면자가항체가저역가이거나음성일경우도 SLE의전형적임상적특징이있다면우선적으로다른질환을배제할경우 SLE로진단할수있다. 반대로자가항체양성이지만임상증상이없는경우에는향후 SLE로발전할가능성은높지만분류기준에는들어가지않는다. 따라서이기준을따르면조기 SLE환자를진단하는데누락될가능성이있다 년 SLICC 분류기준 1997년개정된 ACR기준은현재까지도 SLE 진단기준으로널리이용되지만피부증상에다소편향된기준 ( 광과민성, 뺨발진, 원판상발진, 구강궤양등피부점막관련증상이 11개중 4개차지 ), 세가지이하의분류기준을만족하는비정형적초기환자에서진단의어려움, 신경정신학적분류기준에서발작과정신병두가지만이포함되는점, 그리고활성도를반영하는혈중보체검사의부재등이문제점으로제기되었다 [10]. 즉특이도는높지만 (96%) 민감도는다소떨어지는 (83%) 문제점이있어장기침범이별로없는초기환자를진단하는데한계점이노출되었다. 또한 11개항목에가중치가전혀없이똑같이취급되는모순점이있다. 예를들면조직검사로확진된루푸스신염, 원판상발진, 혈구감소증등이 SLE 환자에서좀더의미를가지는소견으로볼수있는데이에대한가중치반영이없다는점이다. 이런문제점을보완하기위해 SLE 전문가그룹으로구성된 SLICC 에서새로운 SLE 분류기준이 2012년제시되었다 (Table 2). 본분류기준의특징을요약하면첫째, 신생검으로확진된루푸스신염에진단적가중치를두고, 여기에혈청학적으로항핵항체혹은항DNA항체와같은자가항체양성이면 2가지만있어도분류기준에포함시킬수있다는점, 둘째, SLE 활성도평가의척도로사용되는저보체혈증을면역학적기준에포함시키고, 항인지질항체검사로항beta2GP1 항체가추가된점 [9,11], 셋째, 이전기준에서경련이나정신병으로국한되었던뇌신경루푸스를좀더확장해서다발성단신경염 (mononeuritis multiplex), 척수염 (myelitis), 말초혹은두개신경병증을포함하여뇌신경루푸스에대한증상을적극반영한점을들수있다 [4,12]. 이기준에서는임상기준 11가지, 면역학적기준 6가지, 총 17가지항목중 4개이상을충족하면서적어도각각한가지이상의임상기준과면역학적기준을포함하면 SLE로분류할것을제시하고있다. 본기준의검증을위해 SLE 전문가에의해제시된 702예의 SLE scenario를구성하여 1997년기준과비교한결과분류오류를현저히줄일수있었고, 민감도는개선되고 (94% vs 86%), 특이도는거의동등한소견 (92% vs 93%) 을나타내었다 (Table 3). 좀더세부적으로살펴보면 1997년 11개항목중피부점막증상이 4개나포함된문제점을보완해급성혹은아급성루푸스피부병변을 1개항목으로설정하였고반흔이없는탈모증세를별개항목으로분류하였다. 2010년 Gronhagen 등 [13] 이연구한 SLE 환자의피부질환자료에근거하여조직학적소견을강조하였고과거특징적소견으로인식되던뺨발진에대해조직학적으로확진된피부루푸스에대해서만질환관련성이있는것으로강조하였다. 광과민성반응에대해서도다형성빛발진이확인된경우로정의하였고진단에서피부과의사와긴밀한협의가필요함을시사하였다. 과거에는 SLE 환자에서는골미란이없는관절염이특징적소견으로인지되었으나실제로상당수 SLE 환자에서골미란이확인되는경우도있어이번관절염항목에서는골미란에대한언급은하지않았다. 면역학적기준항목에서는 1997년기준에는면역학적이상을한항목으로취급하였으나 2012년기준에서는항핵항체, 항dsDNA 항체, 항Sm 항체, 항인지질항체, 보체감소, 직접쿰스검사양성반응을각각개별항목으로분류하여면역학적기준에좀더가중치를둔것이큰특징이다 [10]

5 - 이상헌. 전신홍반루푸스의새로운분류기준 - Table 2. Clinical and immunologic criteria used in SLICC classification criteria [4] Classify a patient having SLE if The patient satisfies 4 of the criteria listed below including at least 1 clinical and 1 immunologic criteria: or The patient has biopsy-proven nephritis compatible with SLE and with ANA or anti-dsdna antibodies Clinical criteria Acute cutaneous lupus Including lupus malar rash (do not count if malar discoid); bullous lupus; toxic epidermal necrolysis variant of SLE; maculopapular lupus rash; photosensitive lupus rash in the absence of dermatomyositis; or subacute cutaneous lupus (nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory depigmentation or telangiectasia Chronic cutaneous lupus Including classical discoid rash; localized (above the neck); generalized (above and below the neck); hypertrophic (verrucous) lupus; lupus panniculitis (profundus); mucosal lupus; lupus erythematosus tumidus; chillblains lupus; discoid lupus/lichen planus overlap Oral ulcers Palate, buccal, tongue or nasal ulcers in the absence of other causes, such as vasculitis, Behçet s, infection (herpes), inflammatory bowel disease, reactive arthritis and acidic foods Nonscarring alopecia Diffuse thinning or hair fragility with visible broken hairs in the absence of other causes such as alopecia areata, drugs, iron deficiency and androgenic alopecia Synovitis Involving two or more joints, characterized by swelling, effusion or tenderness in two or more joints, and 30 minutes or more of morning stiffness Serositis Typical pleurisy for more than 1 day or pleural effusions or pleural rub; typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day or pericardial effusion or pericardial rub or pericarditis by electrocardiography in the absence of other causes, such as infection, uremia and Dressler s pericarditis Renal Urine protein/creatinine (or 24-hour urine protein) representing 500 mg of protein/24 hour or red blood cell casts Neurologic Seizures; psychosis; mononeuritis multiplex in the absence of other known causes such as primary vasculitis; myelitis; peripheral or cranial neuropathy in the absence of other known causes such as primary vasculitis, infection and diabetes mellitus; acute confusional state in the absence of other causes, including toxic-metabolic, uremia, drugs Hemolytic anemia Leukopenia < 4,000/mm 3 at least once (in the absence of other known causes such as Felty s, drugs and portal hypertension); or Lymphopenia (< 1,000/mm 3 at least once) in the absence of other known causes such as corticosteroids, drugs and infection Thrombocytopenia Immunologic criteria ANA Above laboratory reference range Anti-dsDNA Above laboratory reference range, except ELISA: twice above laboratory reference range Anti-Sm Antiphospholipid antibody Any of the following lupus anticoagulant false-positive RPR medium or high titer anticardiolipin (IgA, IgG or IgM) or anti-β2 glycoprotein I (IgA, IgG or IgM) Low complement Low C3, low C4, low CH50 Direct Coombs test In the absence of hemolytic anemia SLICC, systemic lupus international collaborating clinic; SLE, systemic lupus erythematosus; ANA, antinuclear antibody; ELISA, enzyme linked immunosorbent assay; RPR, rapid plasma antigen

6 - The Korean Journal of Medicine: Vol. 87, No. 4, Table 3. Performance of the proposed classification as compared to the 1997 ACR criteria on the derivation sample based on 702 case scenarios [4] Rule Sensitivity Specificity Misclassified cases 1997 ACR criteria 267/ /392 (93%) 70 (86%) SLICC criteria 292/310 (94%) 361/392 (92%) 49 ARC, American College of Rheumatology; SLICC, Systemic Lupus International Collaborating Clinic. 결 SLE는전신장기를침범하는대표적인전신성자가면역질환으로자가항체형성을특징으로하고이에의한조직파괴가주된병태생리로알려져있다. SLE의발병양상은매우다양하여환자개인마다큰차이를보이고있어진단에어려움이많다. 특히 SLE에서보이는특이자가항체는민감도가높지않고시기마다다르게나타나므로혈청학적진단만으로어려운점이있다. 이런이유로 SLE 분류기준은임상증상및징후와검사실소견을종합해서사용되었다. 최근자가항체법의개발, 조직학적연구가진행되면서분류기준의개정에대한필요성이제기되었고, 1982년과 1997년개정을거쳐 15년만에 2012년새로운기준이발표되었다. 이상적인분류기준이란질병의초기발견이가능하며질환의경과를예측하는데도움이되고, 이를뒷받침할객관적실험실적검사결과를포함하며쉽게적용가능하고, 여러인종및지역에서유효성이검증되어야한다. 조기진단및면역학적검사항목이보강된이번 2012년 SLICC 분류기준은이전기준에비해단점을보완하였고시대적현실을반영하여개정되었다. 새로운 SLICC 분류기준을적용하면이전에 SLE로분류되지못했던환자들이초기부터진단되어치료와모니터링이진행될수있을것으로기대된다. 향후다기관에서비교가능한역학조사와임상연구를통해지속적으로분류기준의유용성및타당성에대한검증이지속되어야할것으로보인다. 론 REFERENCES 1. Hay EM. Systemic lupus erythematosus. Baillieres Clin Rheumatol 1995;9: Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25: Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40: Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64: Fries JF, Siegel RC. Testing the 'preliminary criteria for classification of SLE'. Ann Rheum Dis 1973;32: Piette JC, Wechsler B, Francis C, Godeau P. Systemic lupus erythematosus and the antiphospholipid syndrome: reflections about the relevance of ARA criteria. J Rheumatol 1992;19: Feletar M, Ibanez D, Urowitz MB, Gladman DD. The impact of the 1997 update of the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus: what has been changed? Arthritis Rheum 2003;48: Eilertsen GØ, Becker-Merok A, Nossent JC. The influence of the 1997 updated classification criteria for systemic lupus erythematosus: epidemiology, disease presentation, and patient management. J Rheumatol 2009;36: Ippolito A, Wallace DJ, Gladman D, et al. Autoantibodies in systemic lupus erythematosus: comparison of historical and current assessment of seropositivity. Lupus 2011;20: Yu C, Gershwin ME, Chang C. Diagnostic criteria for systemic lupus erythematosus: a critical review. J Autoimmun 2014;48-49: Mehrani T, Petri M. IgM anti-β2 glycoprotein I is protective against lupus nephritis and renal damage in systemic lupus erythematosus. J Rheumatol 2011;38: The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42: Gro nhagen CM, Gunnarsson I, Svenungsson E, Nyberg F. Cutaneous manifestations and serological findings in 260 patients with systemic lupus erythematosus. Lupus 2010;19: 중심단어 : 전신홍반루푸스 ; 진단

Microsoft PowerPoint - Labs and Lupus Bev2 24

Microsoft PowerPoint - Labs and Lupus Bev2 24 Beverly Johnson MD Rheumatologist Urban Health Plan 1 In the US, it is estimated as many as 1.5 million people have lupus. 1.8 to 7.6 people per 100,000 are diagnosed with lupus each year. Most cases are