类风湿性关节炎英语.docx

1、类风湿性关节炎英语Chapter 286RHEUMATOID ARTHRITISFrank C. ArnettRheumatoid arthritis (RA) is a chronic systemic inflammatory disease predominantly affecting diarthrodial joints and frequently a variety of other organs. TheAmericanCollegeof Rheumatology revised the classification criteria for RA to guarantee

2、uniformity in investigative and epidemiologic studies(Table 286-1). Although these seven items include the most characteristic clinical features of RA, a variety of other disorders may mimic the disease (see Differential Diagnosis andTable 286-3).RA occurs worldwide in all ethnic groups. Prevalence

3、rates range from 0.3 to 1.5% in most populations, but frequencies of 3.5 to 5.3% have been found in several Native American tribes (Yakima, Chippewa, Inuit). The peak incidence of onset is between the 4th and 6th decades, but RA may begin at any time from childhood (see Juvenile Chronic Arthritis) t

4、o later life. Females are two to three times more likely to be affected than males.ETIOLOGY.Despite intensive research over many decades, the cause of RA remains unknown. Three areas of interrelated research are currently most promising: (1) host genetic factors, (2) immunoregulatory abnormalities a

5、nd autoimmunity, and (3) a triggering or persisting microbial infection.Genetic susceptibility to RA has been clearly demonstrated. The disease clusters in families and is more concordant in monozygotic (30%) than dizygotic (5%) twins. Certain major histocompatibility complex (MHC) class II alleles

6、(and their encoded HLA, or human leukocyte antigens) occur with increased frequency in affected individuals. Among white people of western European origin, HLA-DR4 occurs in 60 to 70% of seropositive patients with RA as compared with 25 to 30% of normal individuals. HLA-DR1 is found in the majority

7、of HLA-DR4-negative patients and is most strongly associated with the disease in several other ethnic groups (Israelis, Asian Indians). Several subtypes of HLA-DR4 were initially defined by mixedlymphocyte culture and more recently byDNAsequencing(Table 286-2). Only certain HLA-DR4 subtypes predispo

8、se to RA (Dw4 or DRB1*0401, Dw14 or DRB1*0404, and Dw15 or DRB1*0405), whereas others do not (Dw10 or DRB1*0402 and Dw13 or DRB1*0403). HLA-DR4 subtypes result from only a few amino acid differences in the 3rd hypervariable region of the HLA-DR beta-chain. HLA-DR1 shares this same amino acid sequenc

9、e, as do several other HLA alleles that have more recently been associated with RA in some populations (seeTable 286-2). Thus a shared epitope among several MHC class II molecules appears to predispose to RA. Moreover, homozygosity for the amino acid sequence, especially if carried on HLA-DR4 molecu

10、les, has been shown to correlate with disease severity, including more destructive joint disease, subcutaneous nodules, and extra-articular manifestations, especially rheumatoid lung disease and Feltys syndrome. The crucial region for the shared epitope on HLA-DR molecules appears to be a combining

11、site for the T-cell antigen receptor (TCR). Because MHC class II molecules present processed antigen to the TCR on helper (CD4+) T lymphocytes (seeChapter 270)it appears likely that an abnormal antigen-specific cellular and/or humoral immune response is inherent to theRA appears to be an autoimmune

12、disease, similar to other MHC class II-associated disorders (seeChapter 278). Autoantibodies to the Fc portion of IgG molecules, or rheumatoid factors are present in the blood and synovial tissues of 80% of RA patients. Such cases are termed seropositive. High titers of serum rheumatoid factor typic

13、ally of the IgM isotype, are associated with more severe joint disease and with extra-articular manifestations, especially subcutaneous nodules.Despite the extremely strong association of rheumatoid factors with RA, they clearly do not cause the disease. Production of rheumatoid factor commonly occu

14、rs in other disorders characterized by chronic antigenic stimulation, such as bacterial endocarditis, tuberculosis, syphilis, kala-azar, viral infections, intravenous drug abuse, and cirrhosis. Normal individuals occassionally produce rheumatoid factor, especially with increasing age.An infectious o

15、rigin for RA has been a continuing hypothesis. A variety of bacterial and viral candidates have been proposed and later discarded because of lack of definitive evidence. Viral infections such as rubella,RossRivervirus, and parvovirus B19 have been shown to produce an acute polyarthritis, but no evid

16、ence exists that they initiate chronic RA. Epstein-Barr virus (EBV) remains a viable but unproven candidate for a pathogenetic role because several unusual immune responses to it are found in patients with RA. An EBV protein has also been shown to share the same five amino acids as the HLA-DR4 (Dw14

17、) and HLA-DR1 molecules, which are implicated in susceptibility to RA, thus raising the possibility of molecular mimicry as a mechanism. A similar homology with anEscherichia coliheat shock protein has also been found.PATHOLOGY AND PATHOGENESIS.The pathologic hallmark of RA is synovial membranThe ev

18、ents initiating the process are unknown(Fig. 286-1). The earliest findings include microvascular injury and proliferation of synovial cells, accompanied by interstitial edema and perivascular infiltration by mononuclear cells, predominantly T lymphocytes. Continuation of the process leads to further

19、 hyperplasia of lining cells, both DR-positive type A (macrophage-like) and DR-negative type B (fibroblast-like), and the normally acellular subsynovial stroma becomes engorged with mononuclear inflammatory cells, which may collect into aggregates or follicles, especially around post-capillary venul

20、es. The composition of cellular infiltrates varies, with some being predominantly T cells, usually CD4+ (helper/inducer), and others having a mixed population of lymphocytes (often CD8+ cytotoxic T cells), plasma cells, macrophages, and interdigitating (dendritic) cells. Occasionally, germinal cente

21、rs rich in B lymphocytes can be seen. The proliferating synovium (pannus) becomes villous and is vascularized by arterioles, capillaries, and venules.Roles for bothcellularandhumoralimmune mechanisms in the rheumatoid synovium are supported by molecular and immunopathologic findings. T lymphocytes,

22、chiefly of the TH1 type, appear to be activated, presumably by some unknown antigen(s) presented by DR-positive cells (type A synoviocytes, macrophages, dendritic cells, B lymphocytes). Studies of TCR gene expression suggest restricted Vbeta usage and oligoclonality, but this area is controversial.

23、Collectively, these interacting immune cells produce a variety of cytokines that promote further synovial proliferation and inflammation, as well as bone and cartilage destruction.Importantpro-inflammatory cytokinesappear to be linked in a cascade, with tumor necrosis factor alpha (TNF-alpha) at the

24、 apex promoting the subsequent elaboration of interleukin-1 (IL-1), IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-1 induces the production of metalloproteinases (collagenase and stromelysin) and prostaglandin E2by synoviocytes. This cytokine also promotes the degradat

25、ion and inhibits the synthesis of proteoglycan by chondrocytes, as well as enhances resorption of calcium from bone. At the sametime, there appears to be an attempt by unregulatedanti-inflammatory cytokines,such as soluble TNF receptor, transforming-growth factor beta (TGF-beta), IL-10, and IL-1 rec

26、eptor antagonist, to counterbalance these destructive effects.The ultimate destruction of cartilage, bone, tendons, and ligaments probably results from a combination of proteolytic enzymes, metalloproteinases, and soluble mediators. Collagenase, produced at the interface of pannus and cartilage, is

27、probably largely responsible for the typical bony erosions.CLINICAL FEATURES.The mode of onset of RA is highly variable. In the majority of cases, joint pain and/or stiffness develops insidiously over several weeks to months. One or more small joints of the hands, wrists, shoulders, or knees and/or

28、the metatarsophalangeal (MTP) joints are frequently the 1st symptomatic areas. Malaise and fatigue, occasionally with low-grade fever, may accompany musculoskeletal discomfort. As the disease progresses, joint swelling, tenderness, and a red or bluish discoloration become apparent(Fig. 286-2). The p

29、attern of joint involvement is typically polyarticular and symmetrical and involves the proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, shoulder, knee, ankle, and MTP joints. The distal interphalangeal (DIP) joints of the fingers are usually spared. Joint stiffness, especial

30、ly if lasting more than 1 hour in the morning and after inactivity, is prominent. So characteristic is this symptom that the duration of morning stiffness is often used as a quantitative guide to the activity of the inflammatory process in both clinical practice and research studies. Over time the p

31、atient may experience increasing difficulty with pain and stiffness, as well as impaired joint function. The simple activities of daily living may be severely compromised, and theability to continue a productive occupation is threatened. Sleep habits become disturbed, and the patient may experience

32、depression and weight loss.An acute onset occurring over 1 or several days is seen in about 20% of patients. Occasionally, an individual retires in the evening with no symptoms and awakens with acute, generalized RA. Such a rapid onset of pain involving the joints, surrounding soft tissue, and muscl

33、e can mimic and must be differentiated from acute myositis, viral syndromes, or if focal, even septic or crystal-induced arthritides. Rare patients experience recurrent (palindromic) episodes of acute monarthritis, often so severe as to mimic gout, yet lasting only 24 to 48 hours. Such patients, especially if seropo