Rheumatoid arthritis affects about 1 % of worldwide population. The incidence of this disease increases with age in females, whereas is unusual in men under 45. First-degree relatives of rheumatoid arthritis patients have increased risk of developing rheumatoid arthritis, and siblings of severely affected patients are at highest risk. Monozygotic twins have a concordance rate of about 12-15% but dizygotic twins have only about 3% concordance rate.
Progressive, symmetrical joint destruction is the main clinical feature of rheumatoid arthritis. It is the consequence of autoimmune inflammation, described later in this article. Rheumatoid arthritis, however, is a systemic disease, as shown by the involvement of skin and internal organs, and from the presence of fever and nonspecific laboratory findings of systemic inflammation. Diagnosis is currently based on criteria established by the American College of Rheumatology (Table 2).
Table 2 The 1987 revised criteria* for the classification of rheumatoid arthritis
1. Morning stiffness in and around the joints, lasting one hour before maximal improvement
2. Arthritis of three or more joint areas
3. Arthritis of hand joints
4. Symmetric arthritis: simultaneous involvement of the same joint areas on both sides of the body
5. Rheumatoid subcutaneous nodules
6. Abnormal amounts of serum rheumatoid factor
7. Radiographic changes including erosions or unequivocal bony decalcification localized in, or more marked adjacent to, the involved joints
*Four of seven criteria are required to classify a patient as having rheumatoid arthritis. Criteria 1-4 must be present for at least 6 weeks. Criteria 2-5 must be observed by a physician.
Table 1 Immunological abnormalities which have been described in rheumatoid arthritis
• Hyperactivity of B lymphocytes
• Production of autoantibodies Rheumatoid factor
Antinuclear antibodies: mainly associated with early onset of pauciarticular juvenile arthritis (JA) and with the onset of uveitis
Antiperinuclear and anti-rheumatoid arthritis nuclear antigens (RANA) antibodies. Both associated with EBV Anti-single-stranded DNA: present. Crossreactive between human and other species. No documented diagnostic or pathogenic significance Anti-double-stranded DNA: absent
• Abnormalities in the cytokine network Increased secretion of IL-1, TNFce, IL-6, IL-15, IFN7
TH1 pattern of cytokine secretion from T lymphocytes infiltrating the synovium
• Abnormal immune responses to infectious agents Increased T and B cell responses to EBV antigens Retrovirus-medlated immune dysregulation
Abnormal immune responses to heat shock proteins such as hsp60 and dnaJ
• Antigen-independent mechanisms Synovitis, once initiated, may be self-perpetuating Mutations in the p53 gene
• Role of the shared epitope Binding site for 'arthritogenic' peptides
Responsible for selection and activation of 'arthritogenic' T cells
Pharmacological approach Nonsteroidal antiinflammatory drugs (NSAIDs) and low-dose corticosteroids are currently used for the symptomatic treatment of inflammation in rheumatoid arthritis. Second-line antirheumatic drugs such as antimalarials, sufasalazine, gold, D-penicillamine, azathioprine and cyclosporine are now utilized early in the course of disease to modify its clinical activity. These drugs may stabilize and improve functional activity, including reduction in tender and swollen joint counts and levels of acute phase reactants. The most effective drug available for preventing joint destruction is curently methotrexate. It is often used in combination with other drugs.
Immunotherapy The increasing knowledge of immune mechanisms involved in the etiopathogen-esis of rheumatoid arthritis has led to several attempts to correct immune anomalies by immunotherapy. Most approaches have been based on the usage of monoclonal antibodies specific for certain receptors on immune-competent cells, such as CD4 and CD44. Other targets include inflammatory mediators. Anti-tumor necrosis factor a (TNFa) therapy appears particularly promising. Two alternative approaches, both of extreme interest but as yet at a very preliminary stage, are: 1) gene therapy by intra-articular DNA injection; and 2) oral toleriz-ation to putative targets of the disease process, such as collagen and heat shock protein-derived peptides.
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