RHEUMATOID ARTHRITIS （RA ）Jiang Lindi(Zhongshan Hospital) What is RA? RA is a chronic polyarticular inflammatory arthritis that involves not only small joints of the hands and feet but also systemic organs. Pathologic change: chronic synovitis with pannus ( 血管翳)formation. It will cause bony destruction, deformation, disability if joint inflammation repeatedly occur. RF is present in the sera of more than 75%of patients. The prevalence rate of RA has been estimated to be 0.32%-0.36% in China, Women appear to be affected three times more commonly than men. ETIOLOGY Infectious agents: Epstein-Barr virus, mycoplasma, macobacteria, retroviruses T lymphocyte and macrophage activation B lymphocyte activation Change of the gene expression Molecular mimicry 2. Genetic factors A high incidence among monozygotic twins (30% ~50%),first-degree relative Role of HLA-DR4 in the susceptibility to and severity of RA 70% RA patients ，a relative risk of having RA with HLA-DR4 of 4 to 5 The susceptibility epitope (shared epitope 共同表位): QKRAA 或QRRAA It was considered to be related with the severity of established RA 3. Gender: Predominance in women Improvement or remission of RA during pregnancy 4.Induced factors: tiredness, humidity, cold, mulnutrition, psychical stimuli antigen :HLA-DR(QKRAA) 、heat shock protein 、IgG 、type II collagen antigen processing macrophages +MHCII-peptide complexes presentation T cell cytokine （IL-1 、2、3、4、6 、TNF 、r-INF ）B cell activation immune damage RF and other antibody collagenase 、stromolysin cartilage and bone destruction extra-articular symptom PATHOLOGIC FINDING 1. chronic synovitis In acute phase: effusion and cell infiltration In chronic phase: the number of A type cell remarkably increases the pannus erodes cartilage, bone, ligaments and tendons. 2. extra-articular ：vasculitis 、rheumatoid nodule CLINICAL FAETURES The usually age at onset is 35-50 years The ratio of female to male is 3:1 The onset of RA is usually insidious Systemic symptom of fatigue, malaise, fever, weight loss may be seen 1. Joint manifestation （1）morning stiffness stiffness persisting for over 30 minutes is prominent in the morning or after daytime activity and subsides during the day The persisting length of morning stiffness is associated with the degree of joint inflammation. The duration of morning stiffness is used as the index of disease activity. （2）pain and tenderness ：painful on rest location ：small (PIP,MCP), symmetric joint characteristic ：persisting 、dull or swollen pain （3）swelling ：synovial proliferation, effusion, swelling of soft tissue （4）articular deformity ：ulnar deviation of the fingers, “swan-neck”deformity, atrophy of skin and muscle (see figure1-5) （5）involvement of special joint: atlantoaxial subluxation ，shoulders, temporomandibular joint, hips. （6）Functional capacity 1991 ACR criteria for classification of functional status in RA Class I Completely able to perform usual activities of daily living (self-care, vocational, and avocational) Class II Able to perform usual self-care and vocational activities, but limited in avocational activities Class III Able to perform usual self-care activities, but limited in vocational and avocational activities Class IV Limited in ability to perform usual self-care vocational, and avocational activities 2. Extra-articular manifestations （1）Rheumatoid nodules 20%-30% patients areas that are repeatedly subjected to friction, such as the extensor surface of the forearm The advent indicates the disease is in the active phase （2）rheumatoid vasculitis: episcleritis, scleritis （3）pulmonary manifestation diffuse interstitial fibrosis: abnormal on CT scan, restrictive diffuse pattern intrapulmonary nodules: ：asymptomatic, infected, cavitate rheumatoid pleural disease ：exudative, WBC<5 000/mm3, lower level of glucose (4 ）pericarditis: 30% pericardial effusion, asymptomatic （5）gastrointestinal manifestation: nausea, loss of appetite （6）kidney ：drug-induced ，amyloid degeneration （7）Neurologic manifestations ：A cervical myclopathy can result from atlantoaxial subluxation: sensory abnormity and loss of strength peripheral neuropathies can be produced by proliferating synovium causing compression of nerves and rheumatoid vasculitis: carpal tunnel syndrome. （8）Hematologic manifestations ：anemia, Felty’s syndrome LABORATORY FINDING 1. Anemia: a hypochromic normocytic anemia 2. Elevated ESR and CRP are demonstrated an active condition of the disease 3. Joint fluid examination: WBC in the range 5000 to 20 000/mm3 ，with 50~70% as polymorphonuclear leukocytes , a poor mucin clot, normal level of glucose 6 . RF RF is an IgG,IgA, IgM antibody directed against the Fc fragment RF is Present in the sera of more than 60%-70% patients Despite the extremely strong association of RF’s with RA, they clearly do not cause the disease. RF production occurs commonly in other disorders: syphilis, sarcoidosis, infective endocarditis, tuberculosis, leprosy ,viral infection and parasitic infections, other autoimmune disease (SLE, PSS, DM), healthy people(10%). 7.X- ray changes Class I swollen of soft tissue, juxta-articular osteoporosis Class II joint space narrowing Class III bony cysts and bony erosions Class IV subluxation, fibrous and bony ankylosis 8. Pathologic finding Rheumatoid nodule and synovial biopsy 1988 Revised ARA Criteria for Classification of RA Criterion definition 1.Morning stiffness lasting at least 1hr 2.Arthritis of three at least three joint areas simultaneously or more joint areas having soft tissue swelling or fluid 3.Arthritis of hand joints at least one joint area swollen or above in wrist, MCP,PIP joint 4.Symmetric arthritis simultaneous involvement of the same areas on both sides of the body 5.Rheumatoid nodules 6.Serum rheumatoid factor 7.Radiographic changes including erosions or unequivocal bony decalcification Differential Diagnosis Osteoarthritis: occurs in 40 or more pain increase through day or with use involve DIP, weight-bearing joints radiologic findings: subchondral sclerosis, osteophytes lab findings: normal RA AS HLA-DR4 HLA-B27 women,30-50 years young male Small joint,symmetric lower extremity,asymmetric polyarticular oligoarthropathy wrist, finger sacroilitis,lumbar spine synovitis periarticular soft tissue inflammation ulnar deviation marginal bridging sundesmophytes, swan-neck deformity bamboo spine RF(+) RF(-) TREATMENT The primary objective: Reduction of inflammation and pain Prevention of joint deformity Preservation of muscle strength and joint function Minimizing undesirable drug side effects and improvement of quality of life General approach ：Acute phase: rest and restriction of motion Inactive phase: exercise therapy Drug therapy NSAIDs (nonsteroidal anti-inflammatory drugs) Glucocorticoids DMARDs (disease modifying anti-inflammatory drugs) NSAIDs NSAIDs is used as the first drug of treating RA NSAIDs have analgesic and anti-inflamatory effects but are believed not to be capable of preventing erosions or altering progression of the disease. NSAIDs: ibuprofen,naproxen,sulindac, diclofenac NSAIDs share a common spectrum of clinical toxicities: gastrointestinal tract , kidney, hematopoietic system, central nervous system and liver. Advance Two isoforms of COX have been discovered: COX-1 and COX-2 COX-1 is expressed constitutively in gastric mucosa, Kidney, platelets. COX-2 expression is inducible by cytokines and growth factors in macrophages, monocytes, synoviocytes. COX-2 played a key role in inflammatory conditions Selective COX-2 inhibitors have been developed DMARDs(disease-modifying antirheumatic drugs) DMARDs have the potential to inhibit the abnormal immune response and delay the progression of the disease. DMARDs should be suggested within 3 to 6 months. The time of action will be retarded 3-6 month after taking DMARDs. Careful monitoring for toxicity is required. DMARDs MTX: gastrointestinal and oral ulceration, liver failure,7.5-15mg/qw DP: hematocytopenia, proteinuria, myasthenia gravis, Good-pasture’s syndrome SASP: head ache, gastrointestinal upset ,2- 3g/d Antimalarials: retinal lesion,