儿科幼年类风湿性关节炎 课件

1、 幼年类风湿性关节炎（juvenile rheumatoid arthritis）山东大学齐鲁医院儿科李福海 Summarization of JRAConception of JRA:是以慢性关节炎（chronic arthritis）为特征的儿童病。病变基础(basis of pathology)：关节滑膜(joint synovium)与连接组织(connective tissue)的慢性炎症。关节软骨或软骨下骨组织损伤致永久性关节残疾。发病率（morbidity）:1岁内罕见各年龄组均可发生。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. 感染诱发人群产生异常免疫反应(abnormal immunoreact

4、ivity)。Etiology and pathogenesis感染因素（infection factor)：proofs：病毒感染(viral infection)：关节液中分离出病毒，such as COX V, rubella V, 微小病毒(parvovirus) B19 , EB V,etc.细菌感染(bacterial infection)：enhanced T-cell reactivity to bacterial or mycobacterial, heat shock proteins.Etiology and pathogenesis遗传因素(hereditary fac

5、tor)：proofs：单卵双胎(twins with single ovum)及同胞兄妹(siblings)共患JRA；Pauciarticular type JRA: HLA-B27阳性75；HLAA2与儿童早发的JRA有关。Etiology and pathogenesis免疫因素(immunologic factor)：proofs：JRA不同病期测出不同优势T细胞克隆(T cell colony)，CD4增多；T细胞与巨嗜细胞(phagocyte)过度活化，细胞因子(cellular factor)分泌异常如IL-1，IL-6增加。多数JRA患儿血IgG、IgM、IgA增高，RF10

6、-15positive，ANA positive。超抗原（superantigen）产生: 细菌、病毒的特殊成分，不需抗原提呈细胞加工、处理可直接与有特殊链结构的T细胞受体反应，引起免疫损伤。Etiology and pathogenesis其他因素(others)：寒冷(cold)；潮湿(moisture): Australia provided a much higher prevalence of JRA based on examination by a pediatric rheumatologist.疲劳(fatigue);外伤（traumatic or bone fracture

7、）；精神因素(psychologic fators ) ；营养不良（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(关节软骨破坏).Pathology changes of JRAPeripheral of involved joints presenting tendonitis(肌腱炎), myositis (肌炎), osteoporosis(骨质疏松)，periostitis (骨膜炎)；Serositis (浆膜炎): fibro-pericarditis , pleuritis can occur.Derma change: rash ;Eye changes: irid

10、ocyclitis and uveitis.Classification of JRA第五届儿科免疫学会议将JRA分为4型（1998年）：全身型（systemic-onset of JRA）多关节型(polyarticular JRA)少关节型(pauciarticular or oligoarthritis JRA)伴肌腱附着处炎症关节炎型(associated with tendonitis of arthropathy )Classification of JRA国内教科书分类：全身型(George still disease or systemic-onset disease)少关节型

11、(oligoarthritis or pauciarticular disease)多关节型(polyarthritis)Classification of JRA国际风湿病学联盟儿科专家组建议（2001年）：全身型(systemic-onset disease);多关节炎型（RF阴性）(polyarthritis with seronegative JRA);多关节炎型（RF阳性）(polyarthritis with seropositive JRA);少关节炎型 持续型、扩展型(pauciarticular, persistence and expansion types);银屑病性关节

12、炎(psoriatic arthritis)与附着点炎症相关的关节炎(associated with tendonitis)其他关节炎(other arthritis)Clinical manifestations of JRA全身型JRA (systemic-onset JRA, sys-JRA):约占JRA 20，leukocytosis, anemia;Fever: quotidian(每日热)，驰张高热，为突出特征。Rash: erythematous macular rash, 时隐时现。Arthritis or arthralgia: 出现时间不定。Hepatosplenomega

13、ly and lymphadenopathy:半数出现。 Serositis（浆膜炎）: pleuritis and pericarditis, 1/3患儿出现。Neurosystem signs: 少部分出现。Disseminated intravascular coagulation ,DIC:致死性并发症。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(-)多关节型)：女孩多见(female)，占JRA 2030；表现为关节肿（ede

15、ma）、热(febrile)、痛(pain)、活动受限；关节腔内可有大量渗出;可有滑膜炎（synovitis）。无明显全身表现，可有低热、全身不适等；RF negative；活动性关节炎(active arthritis)可持续数月、数年，可缓解、再发。8090缓解，极少永久损伤。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(+)多关节JRA）：女孩多见,年龄8岁以上；占JRA之10左右；50发生严重arthritis, 关节破坏(joint damage)；药物治疗效果差；易出现皮下类风湿结节（subcutaneous rheumatic nodules )HLA-DR4+高.全身症状：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 (少关节型)：占JRA 40%50%：受累关节(involved joints)4个；多侵犯大关节(elbow, knee, ankle, wrist )，不对称；组织学改变为滑膜炎（synovitis）;临床分两型。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少关节型JRA (pauciarticular typeJRA)：小女孩多见，约占JRA 2030；膝(knee)、踝(ankle)、肘(elbow)等大关节多见，手指关节(finger joints)病变不对称(asymmetry)；髋关节(hip joint)受累少见，不发生骶髂关节炎(hip-

21、iliotitis )；80病程中受累关节4个，20可发展为多关节型；全身症状极少（asymptom）；主要并发虹膜睫状体炎（iridocyclitis）,治疗不当，可失明（blindness）。Clinical manifestations of JRA Pauciarticular or oligoarthritis complicated with chronic iridocyclitis and uveitisClinical manifestations of JRA少关节型JRA (pauciarticular type JRA)：男孩多见，年龄8岁；占JRA 15;大关节受累，

22、髋(hip)关节受累肌腱附着处病变多见(tendonitis)；HLA-B27阳性及阳性家族史；部分发生幼年强直性脊柱炎（juvenile ankylosing spondylitis）;也可发生炎性肠病（inflammatory bowel disease）和Reiter disease。可发生自限性急性虹膜睫状体炎（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类风湿因子（rheumatic factor, RF）:检出率很低，约10；多见于多关节型年长女孩(polyarthritis , elder girls)；常伴有严重关节病变(serious arthropathy)及类风湿结节(rheumatic nodule)；Systemic-onset disease and pauciarticular arthritis : RF negative;75% JRA children hidden RF positive.Supplement exa

25、mination of JRA抗核抗体（antinuclear antibodies, ANA）:Positive 约见于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关节液分析(joint fluid analysis)：可以鉴别化脓性关节炎(septic arthritis)，结晶性关节炎(痛风，gout).滑膜组织学分析（synovial histological analysis）:除外其它疾病。急性期反应物（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：骨质疏松（osteoporosis）,骨膜炎（periostitis）;Late stage：关节骨破坏，尤其腕关节(wrist)；胸部可见胸膜炎（pleuritis）和心包炎(pericarditis);有时可出现风湿性肺病变（rheumatic pulmonary disease）.Supplement exam

28、ination of JRA骨同位素扫描、超声波及MRI:骨扫描(bone scan)可鉴别恶性肿瘤（malignant tumor ）；超声波可发现关节腔渗出及滑膜增厚(synovial hypertrophy)；MRI可发现早期关节病变。 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美国风湿病学会修订：发病年龄16岁以下。1个或几个关节发炎，表现为关节肿胀或积液以及具备下列2种以上体征，如关节活动受限、活动时疼痛或触痛及关节局部温度升高。病程在6周以上。根据起病最初6个月的临床表现确定临床类型：多关节型：受累关节5个或5个以上。少关节型：受累关节4个或4个以下。全身型：间歇发热、类风湿皮疹、关节炎、肝脾淋巴结肿大和浆膜炎；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以少关节炎表现的应除外septic arthritis、osteomyelitis(骨髓炎)、tuberculous arthritis等；全身症状多的应与SLE、rheum

33、atic fever、infectious mononucleosis（传单）、leukemia、septicemia等鉴别；有腰、骶部疼痛者与juvenile ankylosing spondylitis、inflammatory bowel disease等鉴别；JRA合并严重肺部病变时应与bacterial or viral pneumonia鉴别。Treatment of JRA水杨酸制剂与非甾体抗炎药（salicylates and nonsteroidal anti-inflammatory drugs, NSAIDs）:Aspirin （ASP）: 5080mg/kg.d, ti

34、d or qid; 缓解后1030 mg/kg.d, 维持数月；萘普生（Naproxen）: 1015mg/kg.d, bid;布洛芬（ibuprofen）: 50mg/kg.d tid;Side effects:出血（bleeding）;肝脏损害(heptotoxicity) ;胃肠道反应(gastrointestinal irritation) 。Treatment of JRA西乐葆(celebre): 选择性抑制COX-2, 前列腺素减少，显示抗炎镇痛疗效；胃肠道安全性优于NSAIDs, 是治疗中、重度关节炎疼痛的首选；规格：200mg/capsule;儿童用量有待探索，成人200mg

35、, bid.磺胺过敏、aspirin 用后发生哮喘等禁用。Treatment of JRA甲氨蝶呤（methotrexate, MTX）:MTX是抗叶酸制剂；主张早期使用，特别是NSAID无效的全身型或RF阳性的JRA；剂量：10mg/m2，qw；MTX起效时间约312W，病情缓解后维持治疗一段时间；Side effects：Gastrointestinal irritation;Transient aminotransferases elevate;Stomatitis （口腔炎）or digestive ulcer.Treatment of JRA羟基氯喹（hydroxycloroquin

36、e）:剂量：57mg/kg.d，qd.Side effects:视网膜损伤，有观察用1年以上未见眼部疾病发生。Treatment of JRA肾上腺皮质激素（corticosteroid）:Indications: 全身型JRA，伴有iridocyclitis JRA；最小剂量：多关节型用小剂量prednisone:0.10.2mg/kg.d 隔日顿服；全身型：prednisone:0.51mg/kg.d ,顿服； 合并心包炎者prednisone 2mg/kg.d, 渐减量； 甲强龙：1030mg/kg.d qd3d；注意药物副作用，用药时间宜短；甲强龙（methylprednisolone

37、）可减少CD4、CD8T细胞数，两者比例协调。Treatment of JRA美卓乐（medrol): 口服甲基强的松龙；独特的6位甲基化，抗炎活性强;无需肝脏活化（11位羟基化），减轻肝脏负担;9位未氟化，水钠潴留少，对HPA轴抑制作用弱;血浆蛋白结合率恒定，疗效稳定、持久。隔天服用美卓乐后体内糖皮质激素分泌节律与生理状况基本一致。4mg美卓乐地塞米松0.75mg=强地松5mg。Treatment of JRA免疫抑制剂(immunosupressives):CTX (methotrexate)硫唑嘌呤环胞菌素A(cyclosporine A)中医中药：如雷公藤多甙Treatment of

38、JRA治疗方案(therapeutic regimens)：“金字塔”方案(pyramid)：non-steroidal anti-inflammatory drugs, NSAID为第一线药物；青霉胺，磺胺柳氮吡啶，抗疟药、金制剂等慢作用药物(slow anti-rheumatic drugs, SARD )为二线；皮质激素(steroids)，MTX及immunosupressives为三线药物；治疗从一线开始，反应不佳逐渐使用二线、三线药物。缺点：该方案过于保守，贻误时机。Treatment of JRA“降阶治疗”方案(step down bridge）:采取23种药物联合，同类药物中不用2种。NSAID+SARD+MTXNSAID+激素MTX可作为联合治疗首选药物；撤药顺序：首撤激素和NSAID，SARD和MTX可长期维持治疗。部分轻症JRA单用NSAID。Treatment of JRA理疗（physical therapy）：非常必要。眼科治疗：定期眼科裂隙灯检查；Iridocyclitis:皮质激素阿托品；局部用药无效时全身用药或