The Cause of Rheumatoid Arthritis - Essay Example

Running head: Rheumatoid arthritis Rheumatoid arthritis [The of the appears here] [The of appears here] Rheumatoid arthritis (RA) is a chronic multisystem disease of unknown cause. Although there are varieties of systemic manifestations, the charachteristic feature of RA is persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. The potential of a synovial inflammation to cause cartilage damage and bone erosions and subsequent in joint integrity is the hallmark of the disease, but can also affect other organ systems. (Fauci, Longo and Kasper, 2005). The cause of rheumatoid arthritis (RA) is unknown. However, RA involves an attack on the body by its own immune cells (auto-immune disease). Different cases may have different causes. Infectious, genetic, and hormonal factors may play a role. The disease can occur at any age, but it begins most often between the ages of 25 and 55. The disease is more common in older people. Women are affected 2.5 times more often than men. Approximately 1-2% of the total population is affected. The course and the severity of the illness can vary considerably. The onset of the disease is usually gradual, with fatigue, morning stiffness (lasting more than one hour), diffuse muscular aches, loss of appetite, and weakness. Eventually, joint pain appears, with warmth, swelling, tenderness, and stiffness of the joint after inactivity. Joint involvement in RA usually affects both sides of the body equally -- the arthritis is therefore referred to as symmetrical. Wrists, fingers, knees, feet, and ankles are the most commonly affected joints. Severe disease is associated with larger joints that contain more synovium (joint lining). When the synovium becomes inflamed, it secretes more fluid and the joint becomes swollen. Later, the cartilage becomes rough and pitted. The underlying bone eventually becomes affected. Joint destruction begins 1-2 years after the appearance of the disease. Characteristic deformities result from cartilage destruction, bone erosions, and tendon inflammation and rupture. A life-threatening joint complication can occur when the cervical spine becomes unstable as a result of RA. Other features of the disease that do not involve the joints may occur. Rheumatoid nodules are painless, hard, round or oval masses that appear under the skin, usually on pressure points, such as the elbow or Achilles tendon. These are present in about 20% of cases and tend to reflect more severe disease. On occasion, they appear in the eye where they sometimes cause inflammation. If they occur in the lungs, inflammation of the lining of the lung (pleurisy) may occur, causing shortness of breath. Anemia may occur due to failure of the bone marrow to produce enough new red cells to make up for the lost ones. Iron supplements will not usually help this condition because iron utilization in the body becomes impaired. Other blood abnormalities can also be found, for example, platelet counts that are either too high or too low. Rheumatoid vasculitis (inflammation of the blood vessels) is a serious complication of RA and can be life-threatening. It can lead to skin ulcerations (and subsequent infections), bleeding stomach ulcers (which can lead to massive hemorrhage), and neuropathies (nerve problems causing pain, numbness or tingling). Vasculitis may also affect the brain, nerves, and heart causing strokes, sensory neuropathies (numbness and tingling), heart attacks, or heart failure. Heart complications of RA commonly affect the outer lining of the heart. When inflamed, the condition is referred to as pericarditis. Inflammation of heart muscle, called myocarditis, can also develop. Both of these conditions can lead to congestive heart failure characterized by shortness of breath and fluid accumulation in the lung. Lung involvement is frequent in RA. Fibrosis of the lung tissue leads to shortness of breath and has been reported to occur in 20% of patients with RA. Inflammation of the lining of the lung, called pleuritis, can also lead to fluid accumulation. Pulmonary nodules, similar to rheumatoid nodules, can also develop. Eye complications include inflammation of various parts of the eye. These must be screened for in RA patients. http://health.allrefer.com/health/rheumatoid-arthritis-support.html Genetic makeup plays a critical role in susceptibility to RA. Identical twins show 30% to 50% concordance for the disease; first-degree relatives of patients with RA have about a twofold to threefold increased incidence. Study of the major histocompatibility complex (MHC) has identified a shared epitope on the chains of certain HLA-DR haplotypes in RA patients. This susceptibility epitope is associated with the third hypervariable region of DR chains, which contains amino acids 70 through 74 (glutamine-leucine-arginine-alanine-alanine, also known as QKRAA) found in DRB1*0401, DRB1*0404, and other immunologically distinct alleles. This sequence is common to most RA patients, although the disease develops in only a small fraction of those with the epitope. (Gary S. Firestein, M.D, 2004). Susceptibility to RA is likely polygenic; for instance, certain immunoglobulin genotypes and, perhaps, genetic differences in the galactosylation of immunoglobulin may be predisposing factors. Further studies have identified associations with microsatellite alleles of cytokines. Tumor necrosis factor (TNF) alleles are in linkage disequilibrium with the DR gene and may be independent risk factors for RA. In addition, a polymorphism of the interleukin-1 (IL-1) gene is associated with juvenile RA. Studies of IL-10 promoter polymorphisms have been variable, although on balance, there does not appear to be an association between a specific polymorphism and susceptibility to RA. (Gary S. Firestein, M.D, 2004). It is unlikely that a single etiologic factor accounts for all cases of adult RA. A pathogenic organism is often assumed to be responsible, but despite some suggestive data, no conclusive evidence implicates bacteria or mycoplasmas. Viruslike particles have been isolated from synovial effusions in RA, and some RA patients exhibit evidence of a recent parvovirus 9 infection. The potential role of parvovirus 9 is controversial. Whereas some studies have not shown any correlation between RA and serologic evidence of previous infection or presence of 9 genes in synovial tissue, one study demonstrated parvovirus 9 proteins by immunohistochemistry and potentially infectious virus particles in RA synovium. Some data suggest that 9 can infect cultured synovial fibroblasts and increase invasion into cartilage matrix. (Gary S. Firestein, M.D, 2004). Other viruses that have been isolated from synovial fluid include rubella and Epstein-Barr virus (EBV). Sera from most RA patients contain greater amounts of antibodies to various EBV-derived antigens than normal sera. Some RA patients show evidence of autoimmunity long before the appearance of clinical arthritis. For instance, rheumatoid factors and other autoantibodies (e.g., anticyclic citrullinated peptides) can be detected in the blood of patients many years before the onset of disease. Although autoimmunity occurs in patients with RA, it may not be responsible for the initiation of the disease. An alternative hypothesis ascribes the initiation of disease to the activation of innate immunity in the synovium of susceptible persons. This process, which involves primitive pattern-recognition receptors on macrophages, dendritic cells, mast cells, and neutrophils, leads to nonspecific articular inflammation. A local immune response then occurs as the synovium permits the influx of lymphocytes, which, in the appropriate cytokine milieu, recognize a variety of xenoantigens and autoantigens. In this scenario, no single etiologic agent is required. Instead, nonspecific inflammation in a patient with a particular gene set can lead to local responses directed at many articular antigens. The synovial tissue in RA becomes markedly hyperplastic, with redundant folds, frondlike villi, and edema. (Gary S. Firestein, M.D, 2004). In chronic RA, inflammatory cells (including T cells, B cells, macrophages, and plasma cells) accumulate in the sublining region. Lymphocytes can organize into discrete aggregates, although diffuse mononuclear cell infiltration or relatively acellular fibrous tissue can also be present. The majority of T cells are CD4+ memory cells with small nuclei and scant cytoplasm. Although the cells are functionally quiescent, many express surface antigens that suggest previous activation. An increased number of blood vessels remains a prominent finding in the chronic phase. Capillary morphometry studies suggest that the capillary network is more disorganized than normal, and the tissue bulk outstrips the proliferation of blood vessels. Rheumatoid synovitis is usually accompanied by increased synovial effusions. The white blood cell (WBC) count in synovial fluid in active RA is about 10,000/mm3 (about 70% neutrophils). In contrast to the synovium, there are more CD8+ T cells than CD4+ T cells in synovial effusions. Total WBC counts sometimes exceed 50,000/mm3 and include 90% to 95% polymorphonuclear leukocytes. The polymorphonuclear leukocytes are drawn into the joint fluid along a gradient formed by chemotactic substances that include leukotriene B4, platelet-activating factor, the C5a fragment of complement, and chemokines such as IL-8. Lymphocytes, macrophages, and shed lining cells are also seen in synovial fluid. Surprisingly, very few neutrophils are present in RA synovium, even though they are abundant in the effusions. Pannus, the invasive region of synovium that erodes into cartilage and bone, contains macrophages and primitive mesenchymal cells but very few lymphocytes. It is not clear whether these mesenchymal cells are related to type B synoviocytes, but morphologic and functional studies suggest that pannus-derived fibroblasts (pannocytes) have distinctive characteristics (e.g., very high expression of vascular cell adhesion molecule-1). Mesenchymal stem cells have also been described in RA synovial tissue; these cells express distinct surface proteins (e.g., bone morphogenic protein receptors and endoglin) and can migrate into the synovium directly through pores in the bone or through the circulating blood. (Gary S. Firestein, M.D, 2004). Damage to bone and cartilage by synovial tissue and pannus is mediated by several families of enzymes, including serine proteases and cathepsins. The most damaging enzymes are the metalloproteinases (e.g., collagenase, stromelysin, and gelatinase) and cathepsins (especially cathepsin K), which can degrade the major structural proteins in the joint. Cytokines such as IL-1 and TNF- are potent inducers of metalloproteinase gene expression. Although protease inhibitors, like tissue inhibitors of metalloproteinases, are expressed by the rheumatoid synovial lining, the balance between proteases and inhibitors appears to favor the former in RA. Chondrocytes in the cartilage, synoviocytes in pannus, and osteoclasts in the bone are the primary sources of proteases. The receptor activator of nuclear factor B (RANK) and the RANK ligand (RANKL) together play a critical role in local osteoclast activation and bone destruction; the RANKL/RANK system is counterbalanced by the natural inhibitor osteoprotegerin (OPG). In animal models of arthritis, administration of OPG markedly decreases bone destruction, even though inflammation is unaffected. (Gary S. Firestein, M.D, 2004). Destruction of extracellular matrix by rheumatoid synovium mesenchymal cells may occur either as a result of a normal response to the inflammatory cytokine milieu or as a result of abnormal synoviocyte function. Evidence of partial transformation of RA synoviocytes, including adhesion-independent growth and loss of contact inhibition in vitro, suggests that immunosuppression may slow but not necessarily halt joint destruction. Cultured RA synoviocytes that have been coimplanted with cartilage explants into mice with severe combined immunodeficiency disease invade the cartilage matrix, whereas osteoarthritis synoviocytes and normal dermal fibroblasts do not. Somatic mutations in the genes encoding key regulatory proteins, such as the p53 tumor-suppressor gene, may contribute to the transformed phenotype of synoviocytes. Such mutations are likely caused by the high local concentration of oxidants in the rheumatoid joint. Hence, the invasive component of rheumatoid synovitis potentially functions as an autonomous cytokine-independent tissue that erodes into cartilage. Attempts to identify an etiologic agent by determining the proliferative response of synovial T cells to specific antigens have been relatively unrewarding. Articular T cells are often less responsive than peripheral blood cells. For instance, the proliferation of lymphocytes in synovial fluid in response to mitogens or recall antigens (e.g., tetanus toxoid) is significantly lower than the proliferation of blood T cells. Production of cytokines (e.g., interferon gamma and IL-2) by synovial fluid T cells in vitro is also low after stimulation by nonspecific mitogens. The mechanism of defective T cell responses in RA appears to be related to abnormal intracellular redox balance, which interferes with transduction of the T cell receptor signal. Mycobacterial antigens and the 60 kd heat shock protein appear to be exceptions in that lymphocyte proliferation in response to these antigens is greater in cells from rheumatoid effusions than in blood cells. However, this response is not specific to RA and is even more prominent in reactive arthritis. (Gary S. Firestein, M.D, 2004). Immune dysregulation has been observed in peripheral blood T cells in patients with RA, especially with EBV infection. The deficient T cell response can be correlated with disease activity, but it also occurs in patients with other forms of arthritis. A more specific defect is observed in the autologous mixed lymphocyte reaction, in which T cells proliferate and produce cytokines in response to MHC class II antigens expressed on autologous antigen-presenting cells. Autoimmune responses directed toward joint-specific antigens can contribute to synovitis. In addition to type II collagen, which is localized to hyaline cartilage, other articular antigens have been implicated. For instance, T cell immunity directed against heat shock proteins, cartilage protein gp39, cartilage link protein, and proteoglycans have been variably implicated in RA. Many of these antigens can induce arthritis in mice or rats when the animals are immunized with the antigen in combination with complete Freund adjuvant. An unusual T cell phenotype (CD4+, CD28-) has been noted in the synovial tissue of patients with RA that might possess functions of both innate and adaptive immunity. (Gary S. Firestein, M.D, 2004). Rheumatoid factors are immunoglobulins with antibody specificity for the Fc region of IgG. The tests usually employed in clinical diagnosis (latex fixation, sensitized sheep red blood cell agglutination, nephelometry, and enzyme-linked immunosorbent assay) detect only IgM rheumatoid factors. The tests are positive in up to 90% of patients with classic RA, depending on the method used. Although patients with classic RA may have negative test results, a high-titer positive result indicates a poor prognosis -- an unremitting course and a greater degree of joint damage. (Gary S. Firestein, M.D, 2004). IgM rheumatoid factor is most commonly detected; IgG and, less frequently, IgA rheumatoid factors are also sometimes found. The presence of IgG rheumatoid factor is associated with a higher rate of systemic complications. Early studies suggested an unrestricted abundance of cytokines in the rheumatoid joint. However, later experiments demonstrated a relative paucity of many T cell-derived cytokines, including IL-2, IL-4, and TNF-.[29] One exception is IL-17, which can regulate cartilage metabolism and may be produced by CD4+ T cells in the joint.[30] T cells can also potentially contribute to macrophage and synoviocyte activation by inducing metalloproteinase gene expression via direct cell-cell contact. T helper cells can be divided into subsets that mediate distinct functions of the immune system. T helper type 1 (Th1) cells produce interferon gamma and IL-2 but not IL-4, IL-5, or IL-10; T helper type 2 (Th2) cells produce the opposite cytokine profile. Th1 overactivity predominates in most animal models of autoimmunity, whereas Th2 cytokines mediate disease suppression. The small amounts of T cell cytokines that can be detected in RA are biased toward the Th1 phenotype, including IL-17. In contrast, Th2 cytokines (especially IL-4) are virtually absent from the joint. Some IL-10 is present but is derived mainly from macrophages, and the amount is not sufficient to suppress Th1 cytokine production. The relative lack of suppressive Th2 cytokines may contribute to the pathogenesis of rheumatoid synovitis. Levels of other suppressive cytokines, such as the natural IL-1 receptor antagonist (IL-1ra), are also low in RA joint tissues. (Gary S. Firestein, M.D, 2004). Macrophage- and fibroblast-derived cytokines (e.g., IL-1, IL-6, TNF-, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) are abundantly expressed in the rheumatoid joint. Although many of these cytokines are involved in the pathogenesis of RA, TNF- and IL-1 are major pathogenic factors: both can induce synoviocyte proliferation, collagenase production, and prostaglandin release; overexpression of either TNF- or IL-1 can induce arthritis in animal models. IL-15 is produced by macrophages but shares many activities of the T cell-derived cytokine IL-2. It increases the ability of T cells to induce TNF- production by macrophages through an antigen-independent mechanism that involves cell-cell contact. IL-18 is also present in the RA joint and can bias T cell responses toward Th1 or directly activate macrophages to produce proinflammatory mediators. Cytokine networks can potentially establish paracrine or autocrine networks that can perpetuate arthritis long after the etiologic agent has been cleared. Recent studies suggest that anticytokine therapy (including therapy with IL-1, TNF-, and IL-6) is effective in severe RA and demonstrates the importance of fibroblast and macrophage products in chronic synovitis. (Gary S. Firestein, M.D, 2004). The appropriate management of RA is rapidly evolving; previous treatment algorithms based on a gradual escalation of treatment (i.e., the traditional pyramid approach) have been replaced by more aggressive treatment approaches. RA usually requires lifelong treatment, including medications, physical therapy, exercise, education, and possibly surgery. Early, aggressive treatment for RA can delay joint destruction. (Gary S. Firestein, M.D, 2004). Once a diagnosis is confirmed, the current standard of care (in addition to rest, strengthening exercises, and anti-inflammatory drugs) is aggressive therapy with disease-modifying anti-rheumatic drugs (DMARDs). Methotrexate (Rheumatrex) is the most commonly used DMARD for rheumatoid arthritis. Others include leflunomide (Arava), gold thiomalate (Myochrysine), aurothioglucose (Solganal), or auranofin (Ridaura). Anti-inflammatory agents used to treat RA include aspirin and non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen (Motrin, Advil), fenoprofen, indomethacin, and naproxen (Naprosyn). NSAIDS are commonly used to relieve joint pain and inflammation. Although NSAIDs work well, long-term use can cause stomach problems, such as ulcers and bleeding, and possible heart problems. In April 2005, the FDA asked drug manufacturers of NSAIDs to include a warning label on their product that alerts users of an increased risk for cardiovascular events and gastrointestinal bleeding.COX-2 inhibitors block an inflammation-promoting enzyme called COX-2. This class of drugs was initially believed to work as well as traditional NSAIDs, but with fewer stomach problems. However, numerous reports of heart attacks and stroke have prompted the FDA to re-evaluate the risks and benefits of the COX-2s. Rofecoxib (Vioxx) and valdecoxib (Bextra) have been withdrawn from the U.S. market following reports of heart attacks in patients taking the drugs. Celecoxib (Celebrex) is still available, but labeled with strong warnings and a recommendation that it be prescribed at the lowest possible dose for the shortest duration possible. Patients should ask their doctor whether the drug is appropriate and safe for them. Antimalarial medications such as hydroxychloroquine (Plaquenil) and sulfasalazine (Azulfidine) are also beneficial, usually in conjunction with methotrexate. It may be weeks or months before a patient sees any benefit from these medications. Because they are associated with toxic side effects, the patient must have frequent blood tests.Tumor necrosis factor (TNF) inhibitors are a relatively new class of medicatsions used to treat autoimmune disease. They include etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). Adalimumab and etanercept are injectable medications. Infliximab is given by IV. Another relatively new medication is injectible anakinra (Kineret), which is a man-made protein that blocks the inflammatory protein interleukin-1. The drug is used to slow the progression of moderate to severe active RA in patients over 18 who have not responded to one or more of the DMARDs. Kineret can be used with other DMARDs or TNF inhibitors. Other drugs that suppress the immune system, like azathioprine (Imuran) and cyclophosphamide (Cytoxan), are sometimes used in people who have failed other therapies. These medications are associated with toxic side effects and usually reserved for severe cases of RA. Corticosteroids have been used to reduce inflammation in RA for more than 40 years. However, because of potential long-term side effects, corticosteroid use is usually limited to short courses and low doses where possible. Side effects may include bruising, psychosis, cataracts, weight gain, susceptibility to infections, diabetes, high blood pressure , and thinning of the bones (osteoporosis ). A number of medications can be administered with steroids to minimize osteoporosis. http://www.nlm.nih.gov/medlineplus/ency/article/000431.htm Reference: Fauci, Longo and Kasper (2005). Harrison's Principles of Internal Medicine; The McGraw Hill Gary S. Firestein, M.D (2004). Rheumatoid Arthritis from ACP Medicine; Posted 08/19/2004 http://www.nlm.nih.gov/medlineplus/ency/article/000431.htm http://health.allrefer.com/health/rheumatoid-arthritis-support.html Read More