The term “rheumatoid arthritis” (RA) was first proposed by A.B. Garrod in 1858 (Wyngaarde, JB. 1992). It is a chronic, systemic, inflammatory disease predominantly affecting freely movable joints and frequently a variety of organs. Rheumatoid arthritis affects the joints because of the essential role of the synovium in regulating inflammation (Lipsky PE, 2007). RA occurs worldwide in all ethnics groups. The peak incidence of onset is between the 4th and 6th decade, but may begin at any time from childhood to later life. It affects up to 1% of the world’s population and is associated with significant morbidity and mortality (Buch M, 2002). Anthropologic evidence of RA has been found in the New World, but not the Old World skeletons proposing, but no proven that an etiologic agent was carried to Europe by explorers of the Americas. Females are 2-4 times more likely to be affected than males (Koopman WJ, 2001). Nothing was known about RA before the early 19th century. And to this date, the etiology of RA is unclear, and there exists no known specific diagnostic test for it.
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Various articles postulate that “a genetically susceptible host is exposed to an unknown pathogen (antigen), and that this interaction gives rise to a persistent immunological response” (Buch M, 2002). Three areas of interrelated research seem to be most promising: 1) host genetic factors, 2) immuno-regulatory abnormalities and autoimmunity, and 3) a triggering or persisting microbial infection.
Genetic abnormalities in RA has clearly been demonstrated. The disease clusters in families and occurs more frequently in monozygotic than in dizygotic twins with genetic factors accounting for up to 60%of disease succeptibility. “The major histocompatibility complex (MHC) allele (and encoded antigen) HLA-DR4 (HLA, Human Lymphocyte Antigen) is significantly increased in RA patients in most populations” (Arnett, 1992). Arnett explains also that this tissue type is shown to be correlated with rheumatoid factor (FR) titer, severe destruction of joints documented on x-ray, rheumatoid lung disease and Felty’s syndrome.
\Rheumatoid arthritis appears to be an “autoimmune” disease similar to other major histocompatibility complex diseases. Components of the immune system attack the soft tissue that lines the joints and can also attack connective tissue in many other parts of the body, such as the blood vessels and lungs. Eventually, the cartilage, bone, and ligaments of the joint erode, causing deformity, instability, and scarring within the joint. The joints deteriorate at a highly variable rate. Many factors, including genetic predisposition, may influence the pattern of the disease.
An infectious origin for RA has been a controversial hypothesis. Organisms such as Strptococci, diptheroids, mycoplasmas and Clostridium perfringens have all played a part in this controversy and later on discarded because of lack of evidence. Rubella, Ross River Virus and parvovirus have been shown to produce an acute polyarthritis, but still there is no evidence that they initiate chronic RA. The Epstein Barr virus at present still remains a viable but unproven candidate for a pathogenic role.
The pathologic hallmark of RA is synovial membrane proliferation and outgrowth associated with erosion of articular cartilage and subchondral bone. The earliest findings would be microvasculature injury and moderate proliferation of synovial cells. The article of Lipsky in the New England Journal of Medicine describes the pathogenesis as “a dramatic increase in the number of cells in the lining layer, and the sublining layer becomes infiltrated with inflammatory cells, including lymphocytes, macrophages, and mast cells.” But the behavior of the inflammatory cells has not been delineated in great detail.
Cellular and humoral immune mechanism roles in the rheumatoid synovium have been proposed theories, and both have immunologic findings to support the theories (Bush M, 2002). A cellular mechanism would involve activation of infiltrating T lymphocytes by some unknown antigen presented by DR-positive cells. Humoral mechanisms are supported by the demonstration of local RF production within the synovium, the formation of IgM-IgG immune complexes, and activation and consumption of complement via the classic pathway.
Antigen-antibody complexes formed within the joint cavity can become trapped in hyaline cartilage and fibrocartilage, where they cause changes in matrix macromolecules. The ultimate destruction of cartilage, bone, tendons, and ligaments probably results from a variety of proteolytic enzymes, metalloproteinases, and soluble mediators. Collagenase is probably largely responsible for the typical erosions after its activation by plasmin.
Clinical Manifestations and Diagnosis
The general features of RA include synovitis of the synovial joints and deformity. As mentioned in the pathogenesis, RA is due to an abnormal immune reaction associated with constitutional symptoms which can affect the other organ systems as well. However the joint synovitis leading to arthritis affecting multiple joints remains the key clinical feature in RA.
The onset of RA among different individuals is highly variable. In the majority, it takes weeks or months for the joint pain and stiffness to develop. It involves one or more small joints of the hands, wrists, shoulders, or knees and/or the metatarsophalangeal joints. The course of RA, like its onset, also varies widely. Fluctuating disease activity in the disease process is usual. Some patients may have a relentlessly progressive course leading to early disability or even death, but repeated periods of some degree of remission are the rule. Assessment of functional capacity is frequently necessary in the RA patient. The classification for this is as follows: Class I: No restriction of ability to perform normal activities; Class II: Moderate restriction, but with an ability to perform most activities of daily living; Class III: Marked restriction, with an ability to perform most activities of daily living and occupation; Class IV: Incapacitation with confinement to bed or wheelchair (Arnett FC, 1992).
Some of the differential diagnosis of RA include Acute viral arthritis, sarcoidosis, SLE, polyarticular gout, erosive osteoarthritis, polymyalgia rheumatica, psoriatic arthritis, reactive arthritis, polymyositis and calcium pyrophosphate disease. These are differentiated by the presence or absence of subcutaneous nodules and the rheumatoid factor. The findings of subcutaneous nodules and the presence of rheumatoid factor are useful but not specific differential features. To establish a more definite diagnosis, a complete medical evaluation, often including synovial fluid analysis is essential in all patients with joint manifestations.
Articular Manifestations: RA can affect any diarthroidal joint such as the hands, wrists, knees, and feet. It may progress to involve the elbows, shoulders, sternoclavicular joints, hips and ankles. Spinal involvement in always limited to the cervical vertebrae.
Extra-Articular Manifestations: Non-specific symptoms like malaise, fatigue, weakness, low-grade fever and mild lymphadenopathy are common in RA. The extra-articular sites include the skin, as subcutaneous nodules, in the heart as pericardial disease, in the lungs as rheumatoid pleural disease, and neurologic manifestations as compression of nerves such as carpal tunnel syndrome.
Radiologic findings: Radiologic hallmarks of RA include periarticular osteoporosis and focal bone erosions at the joint margins (Lipsky PE, 2005)(Buch M, 2002). Studies attempting to identify the mechanisms underlying the development of focal bone erosions have demonstrated that osteoclasts, predominantly, mediate the bone resorptive process.
Immunological studies are required when RA is being clinically suspected. Tests for rheumatoid factor is always requested. A negative RF does not rule out RA; rather, the arthritis is called seronegative. Rheumatoid factor is frequently negative during the first year of illness. Eventually, about 80% of patients eventually convert to seropositive. A chronic normocytic, normochromic anemia with hematocrit values from 30 to 35% is common. Both serum iron levels and iron-binding capacity are low. The WBC count and differentials are normal, but eosinophilia may occur as the disease progresses. The platelet maybe elevated due the diseases chronicity. Synovial fluid analysis shows a poor mucin clot test and WBC count may be in the range of 5000 to 20,000 per cubic meter. Synovial glucose is usually normal (Arnett FC, 1992).
Objectives of management include 1) relief of pain, 2) reduction of inflammation, 3) minimizing undesirable side effects, 4) preservation of muscle strength and joint function, and 5) returning to a normal lifestyle. Basic initial program that achieves these objectives consists of 1) adequate rest, 2) adequate anti-inflammatory agents, and 3) physical measures to maintain joint function (Arnett FC, 1992). These can only be accomplished by the patient through graded exercise program.
Quality of life is very important in these patients. Health care quality appears to be suboptimal for arthritis, co-morbid disease, and health care maintenance (MacLean CH, 2000). It was observed that patterns of care that included relevant specialists were associated with substantially higher quality. Patterns that included generalists were associated with substantially higher quality health care maintenance than patterns that included neither a generalist nor a relevant specialist. The optimal roles of primary care physicians and specialists in the care of patients with complex conditions should be reassessed (MacLean CH, 2000).
Nonsteroidal Anti-inflammatory Drugs (NSAID’s): Anti-inflammatory drug use is critical to the therapeutic program of the RA patient. Salicylates are inexpensive, generally well-tolerated and effective in controlling inflammation of RA. A constant serum blood level of 20 to 30 mg per deciliter is required. Many other NSAID’s are available and equally effective for RA treatment. New drugs for the treatment of RA include oral leflunomide, subcutaneous injection of either etanercept, adalimumab or anakinra, and intravenous infusion of infliximab (Olsen NJ, 2004).
Significant progress in the pathogenesis of RA has been achieved. Likewise effective new therapy agents have been introduces and tested. Advances for the next 25 years is anticipated, “including delineation of the genetic basis of disease susceptibility and severity, genetic definition of disease subtypes that differ in severity and response to therapy, and prompt initiation of effective individualized treatment based on genetic and environmental assessment. Reconstructive surgery will become increasingly unnecessary and the morbidity, economic burden, and mortality due to RA will be reduced substantially” (Koopman WJ, 2001).
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