兒科幼年類風濕性關節(jié)炎 課件

1、 幼年類風濕性關節(jié)炎（juvenile rheumatoid arthritis）山東大學齊魯醫(yī)院兒科李福海 Summarization of JRAConception of JRA:是以慢性關節(jié)炎（chronic arthritis）為特征的兒童病。病變基礎(basis of pathology)：關節(jié)滑膜(joint synovium)與連接組織(connective tissue)的慢性炎癥。關節(jié)軟骨或軟骨下骨組織損傷致永久性關節(jié)殘疾。發(fā)病率（morbidity）:1歲內罕見各年齡組均可發(fā)生。Summarization of JRAConception of JRA:JRA is on

2、e 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. Three principal types of JRA: polyarthritis; and oligoarthritis (pauciarticular dis

3、ease); and systemic-onset disease. Etiology and pathogenesis Etiology: unknown today ：At 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(abnormal immunoreact

4、ivity)。Etiology and pathogenesis感染因素（infection factor)：proofs：病毒感染(viral infection)：關節(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 pathogenesis遺傳因素(hereditary fac

5、tor)：proofs：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。Etiology and pathogenesis免疫因素(immunologic factor)：proofs：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。多數(shù)JRA患兒血IgG、IgM、IgA增高，RF10

6、-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構的T細胞受體反應，引起免疫損傷。Etiology and pathogenesis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);外傷（traumatic or bone fracture

7、）；精神因素(psychologic fators ) ；營養(yǎng)不良（malnutrition）. Epidemiology of JRAIt is difficult to determine with precision.The incidence of JRA is approximately 14/100,000 children.Different racial and ethnic groups appear to have varying frequencies of the subtypes of JRA.One study reported that black America

8、n children with JRA were older at presentation and less likely to have ANA seropositive or uveitis.Pathology changes of JRAEarly stages: non-specific edema, congestion, fiber exudation, infiltration of lymphocyte .Recurrent attack resulting synovium tissue necrosis, villous hypertrophy and hyperplas

9、ia of the synovial tissue - joint cartilage erosion or damaged(關節(jié)軟骨破壞).Pathology changes of JRAPeripheral of involved joints presenting tendonitis(肌腱炎), myositis (肌炎), osteoporosis(骨質疏松)，periostitis (骨膜炎)；Serositis (漿膜炎): fibro-pericarditis , pleuritis can occur.Derma change: rash ;Eye changes: irid

10、ocyclitis and uveitis.Classification of JRA第五屆兒科免疫學會議將JRA分為4型（1998年）：全身型（systemic-onset of JRA）多關節(jié)型(polyarticular JRA)少關節(jié)型(pauciarticular or oligoarthritis JRA)伴肌腱附著處炎癥關節(jié)炎型(associated with tendonitis of arthropathy )Classification of JRA國內教科書分類：全身型(George still disease or systemic-onset disease)少關節(jié)型

11、(oligoarthritis or pauciarticular disease)多關節(jié)型(polyarthritis)Classification of JRA國際風濕病學聯(lián)盟兒科專家組建議（2001年）：全身型(systemic-onset disease);多關節(jié)炎型（RF陰性）(polyarthritis with seronegative JRA);多關節(jié)炎型（RF陽性）(polyarthritis with seropositive JRA);少關節(jié)炎型 持續(xù)型、擴展型(pauciarticular, persistence and expansion types);銀屑病性關節(jié)

12、炎(psoriatic arthritis)與附著點炎癥相關的關節(jié)炎(associated with tendonitis)其他關節(jié)炎(other arthritis)Clinical manifestations of JRA全身型JRA (systemic-onset JRA, sys-JRA):約占JRA 20，leukocytosis, anemia;Fever: quotidian(每日熱)，馳張高熱，為突出特征。Rash: erythematous macular rash, 時隱時現(xiàn)。Arthritis or arthralgia: 出現(xiàn)時間不定。Hepatosplenomega

13、ly and lymphadenopathy:半數(shù)出現(xiàn)。 Serositis（漿膜炎）: pleuritis and pericarditis, 1/3患兒出現(xiàn)。Neurosystem signs: 少部分出現(xiàn)。Disseminated intravascular coagulation ,DIC:致死性并發(fā)癥。Clinical manifestations of JRAStill disease or systemic-onset of JRA,The girl presents high fever, Salmon-pink macular rash Common physical fin

14、dings Clinical manifestations of JRASalmon-pink macular rash of JRAClinical manifestations of JRAStill disease or systemic onset of JRA,The boy also presents high fever, Salmon-pink macular rashClinical manifestations of JRASeronegative polyarticular JRA (RF(-)多關節(jié)型)：女孩多見(female)，占JRA 2030；表現(xiàn)為關節(jié)腫（ede

15、ma）、熱(febrile)、痛(pain)、活動受限；關節(jié)腔內可有大量滲出;可有滑膜炎（synovitis）。無明顯全身表現(xiàn)，可有低熱、全身不適等；RF negative；活動性關節(jié)炎(active arthritis)可持續(xù)數(shù)月、數(shù)年，可緩解、再發(fā)。8090緩解，極少永久損傷。Clinical manifestations of JRAJoint involvement of JRA: proximal interphalangeal joint involved. However, distal interphalangeal joint rarely involved.Clinical

16、 manifestations of JRASeropositive polyarticular JRA（RF(+)多關節(jié)JRA）：女孩多見,年齡8歲以上；占JRA之10左右；50發(fā)生嚴重arthritis, 關節(jié)破壞(joint damage)；藥物治療效果差；易出現(xiàn)皮下類風濕結節(jié)（subcutaneous rheumatic nodules )HLA-DR4+高.全身癥狀：low fever, retardation, weight loss ,etc.Clinical manifestations of JRAJoint involvement of seropositve polyar

17、ticular of JRA.Sequelae of wrist, knee, and proximal interphalangeal joint.Clinical manifestations of JRAPatient with active polyarticular arthritis. Note swelling (effusions) of all proximal interphalangeal (PIP) joints in addition to bone overgrowth. Also note lack of distal interphalangeal joint

18、(DIP) involvement. The patient has interosseus muscle wasting (observed on the dorsum of the hands), and subluxation and ulnar deviation of the wrists are present. Image courtesy of Barry L. Myones, MD. Clinical manifestations of JRArheumatoild Polyarticular juvenile arthritis typical fever,position

19、 of head, and sequelae.Clinical manifestations of JRAPauciarticular JRA or oligoarthritis (少關節(jié)型)：占JRA 40%50%：受累關節(jié)(involved joints)4個；多侵犯大關節(jié)(elbow, knee, ankle, wrist )，不對稱；組織學改變?yōu)榛ぱ祝╯ynovitis）;臨床分兩型。Clinical manifestations of JRAPatient with active pauciarticular disease. Note significant suprapatel

20、lar swelling (effusion) as well as loss of natural contour medial to the patella. Image courtesy of Barry L. Myones , MDClinical manifestations of JRA少關節(jié)型JRA (pauciarticular typeJRA)：小女孩多見，約占JRA 2030；膝(knee)、踝(ankle)、肘(elbow)等大關節(jié)多見，手指關節(jié)(finger joints)病變不對稱(asymmetry)；髖關節(jié)(hip joint)受累少見，不發(fā)生骶髂關節(jié)炎(hip-

21、iliotitis )；80病程中受累關節(jié)4個，20可發(fā)展為多關節(jié)型；全身癥狀極少（asymptom）；主要并發(fā)虹膜睫狀體炎（iridocyclitis）,治療不當，可失明（blindness）。Clinical manifestations of JRA Pauciarticular or oligoarthritis complicated with chronic iridocyclitis and uveitisClinical manifestations of JRA少關節(jié)型JRA (pauciarticular type JRA)：男孩多見，年齡8歲；占JRA 15;大關節(jié)受累，

22、髖(hip)關節(jié)受累肌腱附著處病變多見(tendonitis)；HLA-B27陽性及陽性家族史；部分發(fā)生幼年強直性脊柱炎（juvenile ankylosing spondylitis）;也可發(fā)生炎性腸?。╥nflammatory bowel disease）和Reiter disease?？砂l(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

23、 pupillary margin to the anterior lens capsule) of the right eye secondary to chronic anterior uveitis. This patient has a 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

24、 Carlos A. Gonzales, Supplement examination of JRA類風濕因子（rheumatic factor, RF）:檢出率很低，約10；多見于多關節(jié)型年長女孩(polyarthritis , elder girls)；常伴有嚴重關節(jié)病變(serious arthropathy)及類風濕結節(jié)(rheumatic nodule)；Systemic-onset disease and pauciarticular arthritis : RF negative;75% JRA children hidden RF positive.Supplement exa

25、mination of JRA抗核抗體（antinuclear antibodies, ANA）:Positive 約見于2030 JRA;Seronegative polyarthritis JRA about 25ANA positive;Seropositive polyarthritis JRA near 75ANA positive;Pauciarticular typeJRA about 50ANA positive;Pauciarticular type JRA children ANA rare positive；ANA positive found most in femal

26、e.ANA may be connected with iridocyclitis in JRA children. Supplement examination of JRA關節(jié)液分析(joint fluid analysis)：可以鑒別化膿性關節(jié)炎(septic arthritis)，結晶性關節(jié)炎(痛風，gout).滑膜組織學分析（synovial histological analysis）:除外其它疾病。急性期反應物（acute phase reactor）:Erythrocyte sedimentation rate(ESR) increased;C-reactive protein

27、 increased.Routine blood test:Anemia, white blood cell and neutrophils increased.Supplement examination of JRAX-ray examinations:Early stage：骨質疏松（osteoporosis）,骨膜炎（periostitis）;Late stage：關節(jié)骨破壞，尤其腕關節(jié)(wrist)；胸部可見胸膜炎（pleuritis）和心包炎(pericarditis);有時可出現(xiàn)風濕性肺病變（rheumatic pulmonary disease）.Supplement exam

28、ination of JRA骨同位素掃描、超聲波及MRI:骨掃描(bone scan)可鑒別惡性腫瘤（malignant tumor ）；超聲波可發(fā)現(xiàn)關節(jié)腔滲出及滑膜增厚(synovial hypertrophy)；MRI可發(fā)現(xiàn)早期關節(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 sur

29、face of the ulnar epiphysis. The view of the left wrist shows 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 ca

30、rpal/metacarpal joints is present. Image courtesy of Barry L. Myones, MD. Diagnosis of JRA1989美國風濕病學會修訂：發(fā)病年齡16歲以下。1個或幾個關節(jié)發(fā)炎，表現(xiàn)為關節(jié)腫脹或積液以及具備下列2種以上體征，如關節(jié)活動受限、活動時疼痛或觸痛及關節(jié)局部溫度升高。病程在6周以上。根據(jù)起病最初6個月的臨床表現(xiàn)確定臨床類型：多關節(jié)型：受累關節(jié)5個或5個以上。少關節(jié)型：受累關節(jié)4個或4個以下。全身型：間歇發(fā)熱、類風濕皮疹、關節(jié)炎、肝脾淋巴結腫大和漿膜炎；除外其他疾病。 Diagnosis of JRA, Arthrit

31、is Rheum 29;174,1986Age at onset 16 year;Arthritis (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 jointsDuration of disease 6 wk or longerOnset type defined by type of disease i

32、n first 6 months:Polyarthritis: 5 or more inflamed joints;Oligoarthritis: 5 inflamed joints;Systemic: arthritis with characteristic feverExclusion of other forms of juvenile arthritis.Differential diagnosis of JRA以少關節(jié)炎表現(xiàn)的應除外septic arthritis、osteomyelitis(骨髓炎)、tuberculous arthritis等；全身癥狀多的應與SLE、rheum

33、atic fever、infectious mononucleosis（傳單）、leukemia、septicemia等鑒別；有腰、骶部疼痛者與juvenile ankylosing spondylitis、inflammatory bowel disease等鑒別；JRA合并嚴重肺部病變時應與bacterial or viral pneumonia鑒別。Treatment of JRA水楊酸制劑與非甾體抗炎藥（salicylates and nonsteroidal anti-inflammatory drugs, NSAIDs）:Aspirin （ASP）: 5080mg/kg.d, ti

34、d or qid; 緩解后1030 mg/kg.d, 維持數(shù)月；萘普生（Naproxen）: 1015mg/kg.d, bid;布洛芬（ibuprofen）: 50mg/kg.d tid;Side effects:出血（bleeding）;肝臟損害(heptotoxicity) ;胃腸道反應(gastrointestinal irritation) 。Treatment of JRA西樂葆(celebre): 選擇性抑制COX-2, 前列腺素減少，顯示抗炎鎮(zhèn)痛療效；胃腸道安全性優(yōu)于NSAIDs, 是治療中、重度關節(jié)炎疼痛的首選；規(guī)格：200mg/capsule;兒童用量有待探索，成人200mg

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

36、e）:劑量：57mg/kg.d，qd.Side effects: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腎上腺皮質激素（corticosteroid）:Indications: 全身型JRA，伴有iridocyclitis JRA；最小劑量：多關節(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；注意藥物副作用，用藥時間宜短；甲強龍（methylprednisolone

37、）可減少CD4、CD8T細胞數(shù)，兩者比例協(xié)調。Treatment of JRA美卓樂（medrol): 口服甲基強的松龍；獨特的6位甲基化，抗炎活性強;無需肝臟活化（11位羥基化），減輕肝臟負擔;9位未氟化，水鈉潴留少，對HPA軸抑制作用弱;血漿蛋白結合率恒定，療效穩(wěn)定、持久。隔天服用美卓樂后體內糖皮質激素分泌節(jié)律與生理狀況基本一致。4mg美卓樂地塞米松0.75mg=強地松5mg。Treatment of JRA免疫抑制劑(immunosupressives):CTX (methotrexate)硫唑嘌呤環(huán)胞菌素A(cyclosporine A)中醫(yī)中藥：如雷公藤多甙Treatment of

38、JRA治療方案(therapeutic regimens)：“金字塔”方案(pyramid)：non-steroidal anti-inflammatory drugs, NSAID為第一線藥物；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；皮質激素(steroids)，MTX及immunosupressives為三線藥物；治療從一線開始，反應不佳逐漸使用二線、三線藥物。缺點：該方案過于保守，貽誤時機。Treatment of JRA“降階治療”方案(step down bridge）:采取23種藥物聯(lián)合，同類藥物中不用2種。NSAID+SARD+MTXNSAID+激素MTX可作為聯(lián)合治療首選藥物；撤藥順序：首撤激素和NSAID，SARD和MTX可長期維持治療。部分輕癥JRA單用NSAID。Treatment of JRA理療（physical therapy）：非常必要。眼科治療：定期眼科裂隙燈檢查；Iridocyclitis:皮質激素阿托品；局部用藥無效時全身用藥或