兒科醫(yī)學—幼年類風濕性關(guān)節(jié)炎

1、幼年類風濕性關(guān)節(jié)炎幼年類風濕性關(guān)節(jié)炎（juvenile rheumatoid arthritis） Summarization of JRAqConception of JRA:n是以慢性關(guān)節(jié)炎（chronic arthritis）為特征的兒童病。n病變基礎(chǔ)(basis of pathology)：關(guān)節(jié)滑膜(joint synovium)與連接組織(connective tissue)的慢性炎癥。n關(guān)節(jié)軟骨或軟骨下骨組織損傷致永久性關(guān)節(jié)殘疾。q發(fā)病率（morbidity）:n1歲內(nèi)罕見n各年齡組均可發(fā)生。Summarization of JRAqConception of JRA:nJRA i

2、s one of the most common rheumatic diseases of children and a major cause of chronic disability. It is characterized by an idiopathic synovitis of the peripheral joints, associated with soft tissue swelling and effusion. nThree principal types of JRA: polyarthritis; and oligoarthritis (pauciarticula

3、r disease); and systemic-onset disease. Etiology and pathogenesis qEtiology: unknown today ：nAt least two events are considered necessary:Immnogenetic susceptibility;External environmental trigger.Specific HLA subtypes have been identified as rendering the child at risk. 感染誘發(fā)人群產(chǎn)生異常免疫反應(yīng)(abnormal immu

4、noreactivity)。Etiology and pathogenesisq感染因素（感染因素（infection factor)：nproofs：病毒感染(viral infection)：關(guān)節(jié)液中分離出病毒，such as COX V, rubella V, 微小病毒(parvovirus) B19 , EB V,etc.細菌感染(bacterial infection)：enhanced T-cell reactivity to bacterial or mycobacterial, heat shock proteins.Etiology and pathogenesisq遺傳因素

5、遺傳因素(hereditary factor)：nproofs：單卵雙胎(twins with single ovum)及同胞兄妹(siblings)共患JRA；Pauciarticular type JRA: HLA-B27陽性75；HLAA2與兒童早發(fā)的JRA有關(guān)。Etiology and pathogenesisq免疫因素免疫因素(immunologic factor)：nproofs：JRA不同病期測出不同優(yōu)勢T細胞克隆(T cell colony)，CD4增多；T細胞與巨嗜細胞(phagocyte)過度活化，細胞因子(cellular factor)分泌異常如IL-1，IL-6增加。

6、多數(shù)JRA患兒血IgG、IgM、IgA增高，RF10-15positive，ANA positive。超抗原（superantigen）產(chǎn)生: 細菌、病毒的特殊成分，不需抗原提呈細胞加工、處理可直接與有特殊鏈結(jié)構(gòu)的T細胞受體反應(yīng)，引起免疫損傷。Etiology and pathogenesisq其他因素其他因素(others)：寒冷(cold)；潮濕(moisture): Australia provided a much higher prevalence of JRA based on examination by a pediatric rheumatologist.疲勞(fatigue

7、);外傷（traumatic or bone fracture）；精神因素(psychologic fators ) ；營養(yǎng)不良（malnutrition）. Epidemiology of JRAqIt is difficult to determine with precision.nThe incidence of JRA is approximately 14/100,000 children.nDifferent racial and ethnic groups appear to have varying frequencies of the subtypes of JRA.nOn

8、e study reported that black American children with JRA were older at presentation and less likely to have ANA seropositive or uveitis.Pathology changes of JRAnEarly stages: non-specific edema, congestion, fiber exudation, infiltration of lymphocyte .nRecurrent attack resulting synovium tissue necros

9、is, villous hypertrophy and hyperplasia of the synovial tissue - joint cartilage erosion or damaged(關(guān)節(jié)軟骨破壞).Pathology changes of JRAnPeripheral of involved joints presenting tendonitis(肌腱炎), myositis (肌炎), osteoporosis(骨質(zhì)疏松)，periostitis (骨膜炎)；nSerositis (漿膜炎漿膜炎): fibro-pericarditis , pleuritis can o

10、ccur.nDerma change: rash ;nEye changes: iridocyclitis and uveitis.Classification of JRAq第五屆兒科免疫學會議將第五屆兒科免疫學會議將JRA分為分為4型（型（1998年）：年）：n全身型（systemic-onset of JRA）n多關(guān)節(jié)型(polyarticular JRA)n少關(guān)節(jié)型(pauciarticular or oligoarthritis JRA)n伴肌腱附著處炎癥關(guān)節(jié)炎型(associated with tendonitis of arthropathy )Classification of

11、 JRAq國內(nèi)教科書分類：國內(nèi)教科書分類：n全身型(George still disease or systemic-onset disease)n少關(guān)節(jié)型(oligoarthritis or pauciarticular disease)n多關(guān)節(jié)型(polyarthritis)Classification of JRAq國際風濕病學聯(lián)盟兒科專家組建議（國際風濕病學聯(lián)盟兒科專家組建議（2001年）：年）：n全身型(systemic-onset disease);n多關(guān)節(jié)炎型（RF陰性）(polyarthritis with seronegative JRA);n多關(guān)節(jié)炎型（RF陽性）(poly

12、arthritis with seropositive JRA);n少關(guān)節(jié)炎型 持續(xù)型、擴展型(pauciarticular, persistence and expansion types);n銀屑病性關(guān)節(jié)炎(psoriatic arthritis)n與附著點炎癥相關(guān)的關(guān)節(jié)炎(associated with tendonitis)n其他關(guān)節(jié)炎(other arthritis)Clinical manifestations of JRAq全身型JRA (systemic-onset JRA, sys-JRA):約占JRA 20，leukocytosis, anemia;nFever: quot

13、idian(每日熱)，馳張高熱，為突出特征。nRash: erythematous macular rash, 時隱時現(xiàn)。nArthritis or arthralgia: 出現(xiàn)時間不定。nHepatosplenomegaly and lymphadenopathy:半數(shù)出現(xiàn)。 nSerositis（漿膜炎）: pleuritis and pericarditis, 1/3患兒出現(xiàn)。nNeurosystem signs: 少部分出現(xiàn)。nDisseminated intravascular coagulation ,DIC:致死性并發(fā)癥。Clinical manifestations of JR

14、AnStill disease or systemic-onset of JRA,nThe girl presents high fever, Salmon-pink macular rash Common physical findings Clinical manifestations of JRASalmon-pink macular rash of JRAClinical manifestations of JRAnStill disease or systemic onset of JRA,nThe boy also presents high fever, Salmon-pink

15、macular rashClinical manifestations of JRAqSeronegative polyarticular JRA (RF(-)多關(guān)節(jié)型多關(guān)節(jié)型)：n女孩多見(female)，占JRA 2030；n表現(xiàn)為關(guān)節(jié)腫（edema）、熱(febrile)、痛(pain)、活動受限；關(guān)節(jié)腔內(nèi)可有大量滲出;可有滑膜炎（synovitis）。n無明顯全身表現(xiàn)，可有低熱、全身不適等；nRF negative；n活動性關(guān)節(jié)炎(active arthritis)可持續(xù)數(shù)月、數(shù)年，可緩解、再發(fā)。n8090緩解，極少永久損傷。Clinical manifestations of JRA

16、nJoint involvement of JRA: proximal interphalangeal joint involved. However, distal interphalangeal joint rarely involved.Clinical manifestations of JRAqSeropositive polyarticular JRA（RF(+)多關(guān)節(jié)多關(guān)節(jié)JRA）：）：n女孩多見,年齡8歲以上；n占JRA之10左右；n50發(fā)生嚴重arthritis, 關(guān)節(jié)破壞(joint damage)；n藥物治療效果差；n易出現(xiàn)皮下類風濕結(jié)節(jié)（subcutaneous rhe

17、umatic nodules )nHLA-DR4+高.n全身癥狀：low fever, retardation, weight loss ,etc.Clinical manifestations of JRAnJoint involvement of seropositve polyarticular of JRA.nSequelae of wrist, knee, and proximal interphalangeal joint.Clinical manifestations of JRAPatient with active polyarticular arthritis. Note

18、swelling (effusions) of all proximal interphalangeal (PIP) joints in addition to bone overgrowth. Also note lack of distal interphalangeal joint (DIP) involvement. The patient has interosseus muscle wasting (observed on the dorsum of the hands), and subluxation and ulnar deviation of the wrists are

19、present. Image courtesy of Barry L. Myones, MD. Clinical manifestations of JRArheumatoild Polyarticular juvenile arthritis typical fever,position of head, and sequelae.Clinical manifestations of JRAPauciarticular JRA or oligoarthritis (少關(guān)節(jié)型少關(guān)節(jié)型)：n占JRA 40%50%：n受累關(guān)節(jié)(involved joints)4個；n多侵犯大關(guān)節(jié)(elbow, k

20、nee, ankle, wrist )，不對稱；n組織學改變?yōu)榛ぱ祝╯ynovitis）;n臨床分兩型。Clinical manifestations of JRAnPatient with active pauciarticular disease. Note significant suprapatellar swelling (effusion) as well as loss of natural contour medial to the patella. Image courtesy of Barry L. Myones , MDClinical manifestations o

21、f JRA少關(guān)節(jié)少關(guān)節(jié)型型JRA (pauciarticular typeJRA)：n小女孩多見，約占JRA 2030；n膝(knee)、踝(ankle)、肘(elbow)等大關(guān)節(jié)多見，手指關(guān)節(jié)(finger joints)病變不對稱(asymmetry)；n髖關(guān)節(jié)(hip joint)受累少見，不發(fā)生骶髂關(guān)節(jié)炎(hip-iliotitis )；n80病程中受累關(guān)節(jié)4個，20可發(fā)展為多關(guān)節(jié)型；n全身癥狀極少（asymptom）；n主要并發(fā)虹膜睫狀體炎（iridocyclitis）,治療不當，可失明（blindness）。Clinical manifestations of JRA Paucia

22、rticular or oligoarthritis complicated with chronic iridocyclitis and uveitisClinical manifestations of JRA少關(guān)節(jié)少關(guān)節(jié)型型JRA (pauciarticular type JRA)：n男孩多見，年齡8歲；n占JRA 15;n大關(guān)節(jié)受累，髖(hip)關(guān)節(jié)受累n肌腱附著處病變多見(tendonitis)；nHLA-B27陽性及陽性家族史；n部分發(fā)生幼年強直性脊柱炎（juvenile ankylosing spondylitis）;n也可發(fā)生炎性腸?。╥nflammatory bowel di

23、sease）和Reiter disease。n可發(fā)生自限性急性虹膜睫狀體炎（iridocyclitis）。Clinical manifestations of JRASequelae of chronic anterior uveitis. Note the posterior synechiae (weblike attachments of the pupillary margin to the anterior lens capsule) of the right eye secondary to chronic anterior uveitis. This patient has a

24、positive antinuclear antibodies (ANAs) and initially had a pauciarticular course of her arthritis. She now has polyarticular involvement but no active uveitis. Image courtesy of Carlos A. Gonzales, Supplement examination of JRA類風濕因子（類風濕因子（rheumatic factor, RF）:n檢出率很低，約10；n多見于多關(guān)節(jié)型年長女孩(polyarthritis ,

25、 elder girls)；n常伴有嚴重關(guān)節(jié)病變(serious arthropathy)及類風濕結(jié)節(jié)(rheumatic nodule)；nSystemic-onset disease and pauciarticular arthritis : RF negative;n75% JRA children hidden RF positive.Supplement examination of JRA抗核抗體（抗核抗體（antinuclear antibodies, ANA）:nPositive 約見于2030 JRA;Seronegative polyarthritis JRA about

26、 25ANA positive;Seropositive polyarthritis JRA near 75ANA positive;Pauciarticular typeJRA about 50ANA positive;Pauciarticular type JRA children ANA rare positive；nANA positive found most in female.nANA may be connected with iridocyclitis in JRA children. Supplement examination of JRA關(guān)節(jié)液分析關(guān)節(jié)液分析(joint

27、 fluid analysis)：n可以鑒別化膿性關(guān)節(jié)炎(septic arthritis)，結(jié)晶性關(guān)節(jié)炎(痛風，gout).滑膜組織學分析（滑膜組織學分析（synovial histological analysis）:n除外其它疾病。急性期反應(yīng)物（急性期反應(yīng)物（acute phase reactor）:nErythrocyte sedimentation rate(ESR) increased;nC-reactive protein increased.Routine blood test:nAnemia, white blood cell and neutrophils increase

28、d.Supplement examination of JRAX-ray examinations:nEarly stage：骨質(zhì)疏松（osteoporosis）,骨膜炎（periostitis）;nLate stage：關(guān)節(jié)骨破壞，尤其腕關(guān)節(jié)(wrist)；n胸部可見胸膜炎（pleuritis）和心包炎(pericarditis);n有時可出現(xiàn)風濕性肺病變（rheumatic pulmonary disease）.Supplement examination of JRA骨同位素掃描、超聲波及骨同位素掃描、超聲波及MRI:n骨掃描(bone scan)可鑒別惡性腫瘤（malignant tu

29、mor ）；n超聲波可發(fā)現(xiàn)關(guān)節(jié)腔滲出及滑膜增厚(synovial hypertrophy)；nMRI可發(fā)現(xiàn)早期關(guān)節(jié)病變。 Supplement examination of JRANote severe loss of cartilage in the intercarpal spaces and the radiocarpal space of the right wrist. A large erosion is present in the articular surface of the ulnar epiphysis. The view of the left wrist shows

30、 boney ankylosis involving the lateral 4 carpal bones with sparing of the pisiform. Erosions are present in the distal radius and ulna. Almost a loss of cartilage has occurred between the radius and ulna and the carpus. Narrowing of the carpal/metacarpal joints is present. Image courtesy of Barry L.

31、 Myones, MD. Diagnosis of JRA1989美國風濕病學會修訂：美國風濕病學會修訂：n發(fā)病年齡16歲以下。n1個或幾個關(guān)節(jié)發(fā)炎，表現(xiàn)為關(guān)節(jié)腫脹或積液以及具備下列2種以上體征，如關(guān)節(jié)活動受限、活動時疼痛或觸痛及關(guān)節(jié)局部溫度升高。n病程在6周以上。n根據(jù)起病最初6個月的臨床表現(xiàn)確定臨床類型：多關(guān)節(jié)型：受累關(guān)節(jié)5個或5個以上。少關(guān)節(jié)型：受累關(guān)節(jié)4個或4個以下。全身型：間歇發(fā)熱、類風濕皮疹、關(guān)節(jié)炎、肝脾淋巴結(jié)腫大和漿膜炎；n除外其他疾病。 Diagnosis of JRA, Arthritis Rheum 29;174,1986nAge at onset 16 year;nArt

32、hritis (swelling or effusion, or presence of two or more of the following signs: limitation of range of motion, tenderness or pain of motion, and increased heat) in one or more jointsnDuration of disease 6 wk or longernOnset type defined by type of disease in first 6 months:Polyarthritis: 5 or more

33、inflamed joints;Oligoarthritis: 5 inflamed joints;Systemic: arthritis with characteristic fevernExclusion of other forms of juvenile arthritis.Differential diagnosis of JRA以少關(guān)節(jié)炎表現(xiàn)的應(yīng)除外septic arthritis、osteomyelitis(骨髓炎)、tuberculous arthritis等；n全身癥狀多的應(yīng)與SLE、rheumatic fever、infectious mononucleosis（傳單）、

34、leukemia、septicemia等鑒別；n有腰、骶部疼痛者與juvenile ankylosing spondylitis、inflammatory bowel disease等鑒別；nJRA合并嚴重肺部病變時應(yīng)與bacterial or viral pneumonia鑒別。Treatment of JRA水楊酸制劑與非甾體抗炎藥（水楊酸制劑與非甾體抗炎藥（salicylates and nonsteroidal anti-inflammatory drugs, NSAIDs）:nAspirin （ASP）: 5080mg/kg.d, tid or qid; 緩解后1030 mg/kg.

35、d, 維持數(shù)月；n萘普生（Naproxen）: 1015mg/kg.d, bid;n布洛芬（ibuprofen）: 50mg/kg.d tid;Side effects:出血（bleeding）;肝臟損害(heptotoxicity) ;胃腸道反應(yīng)(gastrointestinal irritation) 。Treatment of JRA西樂葆西樂葆(celebre): v選擇性抑制COX-2, 前列腺素減少，顯示抗炎鎮(zhèn)痛療效；v胃腸道安全性優(yōu)于NSAIDs, 是治療中、重度關(guān)節(jié)炎疼痛的首選；v規(guī)格：200mg/capsule;v兒童用量有待探索，成人200mg, bid.v磺胺過敏、asp

36、irin 用后發(fā)生哮喘等禁用。Treatment of JRA甲氨蝶甲氨蝶呤（呤（methotrexate, MTX）:nMTX是抗葉酸制劑；n主張早期使用，特別是NSAID無效的全身型或RF陽性的JRA；n劑量：10mg/m2，qw；nMTX起效時間約312W，病情緩解后維持治療一段時間；nSide effects：Gastrointestinal irritation;Transient aminotransferases elevate;Stomatitis （口腔炎）or digestive ulcer.Treatment of JRA羥基氯喹（羥基氯喹（hydroxycloroqui

37、ne）:n劑量：57mg/kg.d，qd.nSide effects:n視網(wǎng)膜損傷，有觀察用1年以上未見眼部疾病發(fā)生。Treatment of JRA腎上腺皮質(zhì)激素（腎上腺皮質(zhì)激素（corticosteroid）:nIndications: 全身型JRA，伴有iridocyclitis JRA；n最小劑量：多關(guān)節(jié)型用小劑量prednisone:0.10.2mg/kg.d 隔日頓服；全身型：prednisone:0.51mg/kg.d ,頓服； 合并心包炎者prednisone 2mg/kg.d, 漸減量； 甲強龍：1030mg/kg.d qd3d；n注意藥物副作用，用藥時間宜短；n甲強龍（me

38、thylprednisolone）可減少CD4、CD8T細胞數(shù)，兩者比例協(xié)調(diào)。Treatment of JRAn美卓樂（美卓樂（medrol): 口服甲基強的松龍；口服甲基強的松龍；v獨特的6位甲基化，抗炎活性強;v無需肝臟活化（11位羥基化），減輕肝臟負擔;v9位未氟化，水鈉潴留少，對HPA軸抑制作用弱;v血漿蛋白結(jié)合率恒定，療效穩(wěn)定、持久。v隔天服用美卓樂后體內(nèi)糖皮質(zhì)激素分泌節(jié)律與生理狀況基本一致。n4mg美卓樂地塞米松0.75mg=強地松5mg。Treatment of JRA免疫抑制劑免疫抑制劑(immunosupressives):CTX (methotrexate)硫唑嘌呤環(huán)胞菌素

39、A(cyclosporine A)中醫(yī)中藥：如雷公藤多甙Treatment of JRA治療方案治療方案(therapeutic regimens)：n“金字塔”方案(pyramid)：non-steroidal anti-inflammatory drugs, NSAID為第一線藥物；n青霉胺，磺胺柳氮吡啶，抗瘧藥、金制劑等慢作用藥物(slow anti-rheumatic drugs, SARD )為二線；n皮質(zhì)激素(steroids)，MTX及immunosupressives為三線藥物；n治療從一線開始，反應(yīng)不佳逐漸使用二線、三線藥物。n缺點：該方案過于保守，貽誤時機。Treatment of JRA“降階治療降階治療”方案方案(step down bridge）:n采取23種藥物聯(lián)合