風(fēng)濕病學(xué)概論

1、 Rheumatology Overview of Rheumatology Rheumatoid Arthritis(RA) Definition: A discipline which mainly focus on diseases that involve skeleton , joint and surrounding soft tissue(e.g. muscle,bursae, tendon and ligament). 1.Diffuse connective tissue disease 2. Spondylitis-associated arthritis 3. Osteo

2、arthritis（osteoarthrosis，degenerative joint disease） 4. Infection-caused rheumatic syndrome 5. Metabolic or endocrine diseases accompanied by rheumatic diseases 6. Tumor 7. Neurotic vascular diseases 8. Bone and cartilage diseases 9. Extra-articular diseases10. Other diseases with articular manifest

3、ation Category of RheumatologyPrevalence (China)number（*ten thousand）RA - 0.34%400AS - 0.26%300SLE - 0.07%65SS - 0.33% - 0.77%800OA - 10.6% 16-30y 14.8% 31-40y3000 29.1% 41-50y 95.9% 60yCommon features of rheumaticdiseasesrecurrent attacks; Clinical symptems: fever, rash, arthritis, hydrohymenitis,

4、lymphadenectasis etc.Multi-system involvement：heart,lung,kidney, digestive system,nervous system ,blood,skeleton and muscle.Serologic examination：many kinds of autoantibody Status of RheumatologyPlenty of patientsMuch misdiagnosis and mistreatmentNot enough specialistsFast developmentTherapeutic pri

5、nciplePatient educationEarly treatmentCombined medicationIndividualized strategyFunction restorationThe classification of rheumatism treatmentNSAIDsDMARDs：SSZ,HCQ etc.immunosuppressive agent：MTX,CTX,LEFglucocorticosteroid（steroids）immunological and biological therapy-target molecule therapy（HLA、TCR

6、vaccine and gene therapy）immunological purging（immunoadsorption）immunological reconstitutionantipodagricscartilage protectantplant medicineEarly Treatment with *DMARDsMechanism of Actionand When to UseTime is everything!*Disease-modifying anti-rheumatic drugs(DMARDs)Rheumatoid Arthritis(RA)A chronic

7、 symmetrical polyarthritis of unexplained cause.-chronic and erosive joint disease It is a systemic disorder characterized by chronic inflammatory synovitis of mainly peripheral joints- autoimmune disorder. Its course is extremely variable and it is associated with nonarthriticular features- involvi

8、ng a variety of major organ systems. Epidemiology of RAAge: the peak age of onset is between 30-50 years old. Gender: M: F1:3 (women are three times more commonly affected than man)Prevalence : affecting from 0.5-3% of the general populationMisdiagonosis rate： 95%Prognosis: time of treatment is ever

9、ything” Prognosis is different based on different starting stage of therapy Disability : 50% in 2- 3 years of onset 70% in 3-5 years of onsetEtiologyThe cause of RA is unknown. A blend of environment and genetic factors is responsible：Genetics：HLA-DR4、HLA-DR1、HLA-DQA1Infectious influence：EB virus、pa

10、rvovirus-Others：hormonal milieu(estrogen).Environmental influence ：cold、moisture、fatigue、psychostimulant, etc Unknown:antigen person with special genetics antigen-specific responses autoimmune diseasePathogenesis Course of RA 50 patients with early RA followed by Masi for 6 years, the results showed

11、 that: monocyclic 20%polycyclic 70%progressive 10%pathologySynovitis-The basic pathologic event in RA synovitis bone and cartilage progressively eroded and destroyed synovitis extra-articular damage Synovial pannusPathology 1. articular manifestations: synovitis; hypertrophic synovium; pannus;subcho

12、ndral bone lost; joint destruction , deformity and disability 2. nonarticular manifestations:vasculitis; subcutaneous nodules; pericarditis; pulmonary nodules or interstitial fibrosis; mononeuritis multiplex; episcleritis or scleritis, etc Clinic manifestation(一) -articular manifestationCharacter：ch

13、ronic、symmetric、polyarthritis（pain、tenderness、swollen 、dysfunction）Morning stiffness：1 hour，its duration correlate with the level of inflammationClinic manifestation(一) -articular manifestationCommon sites：Joints most often affected (Proximal interphalangeal joints, metacarpophalangeal joint, wrists

14、)More affected Joints (foot and ankle, knee, elbow)Joints may also affected (cervical spine, shoulders, hips, temporomandibular joint) At least 3 of 14 joints have had soft tissue swelling or fluid Clinic manifestation(一) -articular manifestation Typical sign of hand RA ：Synovial swelling（early RA）

15、ulnar deviation, swan-neck deformitis, boutonniere deformity（late RA） At least one joint area affected among wrist , metacarpophalangeal and Proximal interphalangeal jointsAttentionThe main character of RA: chronic and symmetric two hands arthritis with morning stiffnessA single positive RF do not a

16、llow a definite diagnosis of RAA positive X ray is important to the diagnosis of RAExclude other articular disease when making a definite diagnosisulnar deviationswan-neck deformitisClinic manifestation(二) -Extraarticular manifestationsSystemic features： fever, fatigue, anemia, weight loss and depre

17、ssionRheumatoid nodule： indicating active RA or serious arthritisRheumatoid vasculitisCardiac manifestation: pericarditis, mycartitis, valvular diseaseClinic manifestation(二) -Extraarticular manifestationsRespiratory manifestation： fibrosis，pleural disease or nodular lung diseaseNeurologic manifesta

18、tions：entrapment neuropathiesHematological manifestation, gastrointestinal manifestations and renal manifestations almost caused by therapysjogrens syndrome.Rheumatoid nodulesNecrosisClassification of X ray X-ray have a important role in the diagnosis , classification and monitor of RA stage：osteopo

19、rosis, swelling of extraarticular soft tissue stage：narrowness of joint space stage ：cartilage and bone destruction in addition to osteoporosis stage ：hyperextension ,fibrous or bone ankylosisDiagnosis of RAMainly by the clinic manifestation and signs joints affected （wrist、PIP、MCP、elbow、 temporoman

20、dibular joints） morning stifness, subcutaneous nodule, systemic manifestation2. Laboratory tests is helpful to the diagnosis positive autoantibody hypergammaglobulinemia3. Atypical RA early，monoarticular，asymmetric4 . Special types of RA RS3PE, Palindromic5. Right use of criteriaSpecific antibodys i

21、n the diagnosis of RANameSensitivity(%)Specificity(%)RFRA33/36 antibodySA antibodyAKAAPF(antiperinuclear factor)CCP antibodyInsidious RF50-70 25-45373348-9260-705089 99.678-9787-9570-909870-90Laboratory features of RA High elevation in active RAElevation correlated with IgM-RFmicrocytic hypochromic

22、anemia with normal ironNormal or mild elevationElevation in serum but decreased in synovial fluidNormal or mild elevationImmunoglobulinImmunocomplex g globulinthrombocyteCold globulinRBCWBCZincC3, C4itemsSignificance in RALaboratory features of RA1、autoantibody RF，CCP antibody2、Tests correlated with

23、 Ig ESR、IgG、IgA、IgM，CIC，protein electrophresis3、normal tests blood routine test, urine routine test, liver/kidney function tests4、genetics HLA-DR4/DR1The 1987 ARA criteria for the classification of rheumatoid arthritisArthritis (soft tissue swelling) of 3 or more joints observed by a physicianArthri

24、tis in at least one of wrist, MCP or PIP jointSymmetric arthritis Morning stiffness in and around joints lasting at least 1 hour before maximal improvementSubcutaneous nodules Positive test for rheumatoid factorRadiographic erosions or periarticular osteopenia in hand or wrist joints Criteria 1 thro

25、ugh 4 must have been present for at least 6 weeks Diagnosis of early, milder and atypical RATo take necessary examinationsImaging techniques (X-ray 、CT、 MRI）Synovial fluid analysis synovial tissue analysisDiagnosis of early RAIt is especially important in guiding therapy and improving prognosis of R

26、ALack of the definition of early RA among rheumatologist The criteria for very early RA and early RA provided in EULAR meeting in 2003 as following:Very early RA：RA course less than 12 weeksEarly RA：RA course between 12 weeks and two yearsOnce the diagnosis is made, the patient should be given DMARD

27、s Laboratory testAnti-cyclic citrullinated peptide (CCP) antibodyMagnetic resonance imaging (MRI)Anti-cyclic citrullinated peptide (CCP) antibodyStudy by VallbrachtThe sensitivity of Anti-CCP was 51 with high specificity(97) in diagnosis of RAAnti-CCP level decreased during the pulse therapy of DMAR

28、Ds and corticosteroidAnti-CCP may be a useful marker for disease activity in RA and could be used to guide RA therapyAnti-cyclic citrullinated peptide (CCP) antibodyStudy by N.C.KyiazisAnti-CCP is a specific marker antibody for diagnosis of RAThe sensitivity of anti-CCP nearly equal to that of IgM R

29、F In early RA：anti-CCP is more sensitive than IgM RFIn RA diagnosed：IgM RF is more sensitive than anti-CCPIn RA patients with negative IgM RF ,more than 1/3 patients with positive anti-CCP N.C.Kyiazis,et al.THU0215 Anti-cyclic citrullinated peptide antibodies and rhermatoid factor in the diagnosis o

30、f early versus established rheumatoid arthritis. Anti-cyclic citrullinated peptide (CCP) antibodyAnti-CCP play a important role in the diagnosis of RAThe value of Anti-CCP in the diagnosis of early RA is certain by rheumatologists in Europe and USA , this Ab was listed to the routine tests of RAMagn

31、etic resonance imaging (MRI)For five years follow-up studies in Denmark stergaard found thatMRI of wrist may find early bone erosion and can demonstrates bone erosion two years early than routine x-rayCompared with plain radiography, MRI of wrist showed more good sensitivity in screening articular d

32、isease of RA and was useful to early diagnosis of RADiagnosis of active RA（for new drug study）Moderate pain in restMorning stiffness1 hourMore than three joints swellingTenderness eight joints ESR28mm/h Four of five items should be satisfiedPrognostic indicators of RA 1. Gender：man have a good progn

33、osis compared with woman in general2Age：young woman have a poorer prognosis3Affected joints number: 20 when onset or accumulated 4. Bone erosion happening in two years, or more accumulated bone erosionPrognostic indicators of RA5Loss of joint function earlier (one year after onset) and accumulated i

34、ncrease6Five years history of RA when accepting therapy7Rheumatoid nodules8High titer of rheumatoid factorPrognostic indicators of RA9Extraarticular manifestations 10High ESR, CRP and Eosinophil in blood11Metatarso-phalangeal synovitis(bone erosion)12Serious Systemic symptoms：(fever, fatigue, anemia

35、, weight loss and depression)13Early glucocorticoid therapy (short time) can not relieve symptoms completely and 10mg prednisone per day can not control diseaseDifferential diagnosisRheumatic arthritisosteoarthritisAnkylosing spondylitisgoutSystemic lupus erythematosus Condition of RA in China One p

36、henomenon： too many misdiagnosis and wrong therapy one misleading： RA can not be completely recovery general principles of management : therapy under rules RA Treatment Theres no radical treatment at present. Therapeutic aim:Relieve symptoms,especially arthralgiaControl or postpone the progress of t

37、he disease and prevent osteoarthritic destruction.Maintain the normal function of the joints. Promote the restoration of the joints,in order to prolong the catabatic course. The therapeutic principle of RA1、Education2、Early treatment 3、Combination of drugs application4、Individualized therapy5、Functi

38、onal activityEducation of RA patients1、Feature of dicease：chronic destructive arthritis2、The application of drugs：first-line drugs and second-line drugs3、Functional exercise: functional exercise of the joints is emphasized.4、Attention：recheck blood test and liver function5、Follow-up at out-patient c

39、linic:every 4 to 8 weeks .Therapeutic methods General treatment:Rest and reasonable arrangement of activity;Therapeutic exercises of joint （functional exercise of the joints） should be attached importance to;Physical therapy;Individualized treament the key point of RA treatmentClinical feature(multi

40、 articular vasculitis)Laboratory chemical examination (the spectrum of antibodies, HLA-DR)Drug history Drug responseToleranceEconomic statuscomplianceThe treament should be effective, of few adverse effect and favorable compliance. Functional exercise - never negligibleNew forms of NSAIDs Enteric co

41、ated tablet：Votalin Extentab：Indocontin(Indometacin) ,Antine（Diclofenac Enteric-microcapsulated capsule：Difene （Diclofenac ）,Clinoril（Sulindac , Zulida）, Relafen, Maxicom （Nabumetone） Complex form：奧濕克（Misoprostol+Diclofenac） External form：Votalin Emulgel , Etofenamate , fenbid emulgelCOX 概念 ( 1995 )

42、花 生 四 烯 酸 血栓素 A2 前列環(huán)素 前列腺素 E2 (血小板) (胃腸粘膜) (腎)炎性前列腺素促發(fā)炎癥非甾體類藥物副 作 用抗炎鎮(zhèn)痛作用生理保護(hù)功能內(nèi)毒素 , 細(xì)胞因子 ,有絲分裂原抑 制抑 制激 活COX-1COX-2Cyclo-oxygenase(Cox)Physiological function NSAIDS general NSAIDS Votalin,Kaflan, Difene ,Clinoril ,Naproxen,Ibuprofen prone COX2 inhibitor Nabumetone（Maxicom、Relafen）,Mobic、 Nimesulide,

43、Etodolac selective COX2 inhibitor celebrex（Celecoxib）,vioxx（Rofecoxib）, Etocoxib,COX189NSAIDS first-line drugs soon control the role of inflammatory transmitter， relieve joint swelling and arthralgia as well as morning stiffness relieve constitutional symptoms seldom cause severe adverse effectThe e

44、ffect of NSAIDs on cartilage 1. NSAIDs that may damage cartilage： Aspirin、Indometacin、butazone 2. NSAIDs that have no adverse effect on cartilage： Sulindac, Piroxicam 3. NSAIDs that accelerate cartilage metabolization： Votalin ,Benoxaprofen、Tenidap （hasnt come into home market yet ）Glucocorticostero

45、id(steroids)Misuse：abuse disuseRecognition of GC effect in RA treatment Boers (Lancet, 1999); Emery (Lancet, 1997)Small dosage (7.510mg per day ), reduce dosage as early as possible.2. Add DMARDS simultaneously .3. Add calcium and Vitamin D.4. Take indications into strict control: （1）ineffective wit

46、h regular treatment （2）patients with vasculitis （3）function as a “Bridge” （4）local applicationThe assessment of small dosage steroids in RA treatment is an impressing hotspot in annual conference of 2004.Multi-aspect research has been carried through on the effect of RA treatment with small dosage s

47、teroids （prednisone） and its long-term effect as well as adverse effect . Conclusions are:Steroids should be used in small dosage( i.e. 2.5-10 mg/d). Pincus etc in US reported that extremely low dosage of prednisone （3mg/d） can remarkably ameliorate the arthritic and systemic symptoms of RA patients

48、. 。Steroids Steroids Small dosage of steroids can relieve the bone destruction of RA and function as DMARDs to a certain extent.The incidence of diabetes and hypertension has no increase in RA patients when receipting treatment with small dosage of steroids. Small dosage of prednisone may increase t

49、he incidence of osteoporosis,but it needs further double-blind random trial study. Patients can benefit from addition of calcium and vitamin D synchronously.Steroids Small dosage of steroids should not be used alone in treating RA. DMARDs should be added to control the disease.Take indication into s

50、trict control. Choose patients carefully.Though it has been relatively common in treating RA with small dosage of steroids,the recognition and application is still disputing.Intraarticular injection of GC has already been applied to treat RA.SteroidsJ.Natour (Brazil)in EULAR of 2005 proposed the res

51、earch on therapeutic effect and side-effect of triancinolone given in intraarticular injection and applied in systemic treatment. J.Natour found out thatIntraarticular injection has better therapeutic effect ,few side-effect and less suppression for ACTH secretion compared with systemic treatment .

52、1. DMARDs 2.immunosuprressor agent 3. steroids 5. Biological agent1980s Applied when NSAIDs is ineffectiverarely applied Not tandardized not applied Early, combined (MTX、SSZ、HCQ）Early,individualizedSmall dosage, take indication into strict controlEtanercept , Infliximab etc. The transition of RA the

53、rapeutic strategyEarly treatment(ET)advanced stageDiseaseattacks window phaseCause deformity or deaththe early stageMRI / X-ray evidence(3 months)Comparative study on combination therapy of MTX,SSZ and HCQ authorODell(2002)Kremer(2000)Mottoen(1999)ODell(1996)double-blind , random 1. MTX+SSZ+HCQ2. MT

54、X+SSZ3. MTX+HCQdouble-blind , random 1. MTX+SSZ+HCQ2. MTX3. SSZ+HCQmulticentre ,random1. SSZ+MTX2. SSZ(MTX or HCQ or pred)multicentre, double-blind 1. LEF+MTX2. PLC+MTXMTX 7.5-17.5mg/WHCQ 0.2 BidSSZ 0.5-1.0 BidMTX 7.5-17.5mg/wSSZ 0.5g BidHCQ 0.2g BidSSZ 1.0g/d HCQ 0.3g/dpred 5mg/dLEF(100mg2，20mg-10m

55、gQd)MTX 16.7mg/wtrigeminy bigeminy(MTX+HCQMTX+SSZ)trigeminy bigeminysinglebigeminysingleLEF+MTXPLC+MTXresearch designusageassessment of effectDMARDS combination treatment(Littlejohn, Piet，1997-2000)*1. SSZ+ MTX*2. SSZ + HCQ+MTX*3. SSZ + HCQ 4. MTX+ SSZ +gold preparation 5. SSZ + HCQ+ PEN*Leflunomide

56、、ciclosporin (CsA),（prednisone）(DMARDS) in common useSulfasalazine(SSZ） 2-3g/dMethotrexate (MTX） 7.5-20mg/wLeflunomide (Lef） 10-20mg/dhydroxychloroquine（HCQ） 0.4/dPenicillamine（Pen） 0.5-0.75/dAuranofin（Ridaura） 6mg/dciclosporin A（CsA） 50-100mg/d come into effect slowly,have a long-lasting effect and

57、 avoid progress of synoviumThe comparison of ACR RA treatment guide in 1996 and 20021996drugmaintenance dose2002drugsmaintenance doseHCQSSZMTXAzaD-pen Gold0.2 Bid1.0 Bid or Tid7.5-15mg/W50-150mg/d250-750mg/d3mg BidHCQSSZMTXLeflumomideEtanerceptInfliximabMinocylineCyclosporineImmunoadsorptionAzaD-pen

58、Gold0.2 Bid1.0 Bid or Tid7.5-20mg/W20mg/d or10mg/d25mg 2/W3-10mg/4-8W0.1 Bid2.5-4mg/kg/d1/W 12 50-150mg/d250-750mg/d3mg Bidalter/ increase DMARDsAdd MTXMTXIneffective with MTXDrug combinationOther singleagentbiological agentDrug combinationDiagnose RA in an early stage note the disease activity inde

59、x assess prognosis EducationStart DMARDs within 3monthsApply NSAIDs when requiredSmall dosage of steroids can be pplied in localized way or orallyPhysical therapy /exercise therapyAssess the reactiveness of the disease regularlyThe revised ACR treatment guide of 2002effectiveineffective(3 months)Ine

60、ffective with multi-kinds of DMARDsJoint destructionoperationThe treatment of refractory RA1 、New forms of immunological and biological agent2 、Immunological purification3 、T cell vaccine4 、Stem cell transplantation5、 Gene therapy、Surgical operation in advanced stageBiological agentTNF antagonist Th