D. Kilimozhi, V. Parthasarathy* and Manavalan R
Department of Pharmacy, Annamalai University, Annamalai Nagar-608002, Tamil Nadu, India
*Corresponding Author E-mail: firstname.lastname@example.org
Arthritis is a chronic auto immune disorder that may affect many tissues and organs, skin, blood vessels, heart, lungs and muscles but principally attack the joints, producing a non suppressive proliferative and inflammatory synovits1 that often progress to destruction of the articular cartilage and ankylosis of the joints2,3. Although the cause of arthritis remains unknown, auto immunity plays a pivotal role in its chronicity of and progression
Historical Concepts and Definition
RA was first described in 1800 as a new form of gout under the designation “primary asthenic gout”. Arthritis (from Greek: [arthrosis] meaning joint; and suffix –it is meaning inflammation) is literally the inflammation of the joints4. Thus, RA is a systemic chronic inflammatory disorder of cyclic nature that affects mainly synovial joints5. The author identified several distinctive characteristics of the disease, including predominance in women, a chronic course, involvement of many joints from the onset and a decline in general health6.
Several studies in various countries have investigated the prevalence and incidence of RA and a considerable variation between different populations has been found. However, in Northern Europe and North America a prevalence of 0.5-1% with an annual incidence of 20-50 new cases per 100,000 inhabitants is usually reported7. There are no studies on RA incidence from developing countries. Previous studies from Japan suggested a relatively higher incidence of the disease, but all of them were based on previous identification criteria, and recent data do not confirm this picture8.
These values seem to have decreased compared to older ones9,8 however it is not clear whether this is a true reduction or merely a reflection of different methods used to identify RA patients7. RA has also been shown to reduce life expectancy by 3-10 years depending on severity of the disease and age at onset10. The increases in life expectancy recorded in the general population over the past decades are not reflected in RA patients11,12. The causes of death do not differ significantly between RA patients and the general population, but they occur at a younger age7.
The annual incidence rates of RA very between 20 and 5 cases per 100,000 inhabitants in north American and north European countries13-15. There are only few studies from southern European countries indicating a relativity lower occurrence of the disease9. There are no studies on RA incidence from developing countries. Previous studies from Japan suggested a relatively higher incidence of the disease, but all of them were based on previous identification criteria, and recent data do not confirm this picture.
A joint is where two or more bones come together, such as the hip or knee. The bones of a joint are covered with a smooth, spongy material called cartilage, which cushions the bones and allows the joint to move without pain. The joint is lined by a thin film of tissue called the synovium. The synovium's lining produces a slippery fluid called synovial fluid that nourishes the joint and helps reduce friction16. Strong bands of tissue, called ligaments, connect the bones and help keep the joint stable. Muscles and tendons also support the joints and enable to move.
With arthritis, an area in or around a joint becomes inflamed, causing pain, stiffness17 and sometimes are difficult to move. Some types of arthritis also affect other parts of the body, such as the skin and internal organs.
3.1 Etiology and Risk Factors:
It is believed that RA is triggered when an immunogenetically susceptible host is exposed to an antigen. In this manner, an acute inflammatory reaction is initiated18. In contrast to the normal course of inflammation, when the antigen has been repelled, this reaction is not terminated. Instead, it recognizes some of the tissues in the joints as foreign and attacks them, called as autoimmune reaction. This chronic uncontrolled phase of the inflammation that ultimately destroys the joints. The antigen(s) that triggers the initial inflammation has not been positively recognized; however, several potential risk factors have been identified and are discussed below.
3.2. Genetic Susceptibility:
Studies have found that high rates of concordance between monozygotic twins19 and first-degree relatives of RA patients20 suggesting a definite genetic predisposition to RA. However, the failure to demonstrate Mendelian inheritance patterns indicates interplay of multiple genetic factors21,12. The most consistent genetic association of RA is with the human leukocyte antigen (HLA) alleles20,12. HLA is a part of the major histocompatibility complex (MHC) of genes, located in chromosome six18. Its main function is to encode molecules (Class I and II) responsible for presenting T-cells, a lymphocyte sub-type of the immune system capable of destroying virally infected cells with viral or other peptides. The majority of individuals who develop RA (65%-80%) have the HLA-DR4 or DR1 allele or both22,23,24. All the DR alleles associated with RA share a common region of four amino acids located in the antigen-binding cleft of the DR molecule adjacent to the T-cell receptor2). This is referred to as “the shared” or “the rheumatoid epitope”7 and is presumably the specific binding site of the antigen that initiates the inflammation of the joints20. Differences in genes of various proteins eg cytokines implicated in the course of RA have also been studied; however, their results were not consistent between different populations22. This indicates that, in addition to HLA, the development and progression of RA is influenced by a complex genetic profile.
3.3. Age and Gender:
Even though RA is not age or gender specific, differences between age groups and genders exist. Most epidemiological studies suggest an age of disease onset during or after the fifth decade of life9,8,7. However, no age is immune to RA as even young children can suffer from it5. Females are two-three times more likely to develop RA compared to males13,15 ,7.
3.4. Hormones in arthritis:
The above mentioned gender difference as well as the observations that pregnancy has an ameliorating effect on RA and that RA patients are more likely to be nulliparous before disease onset compared to the general population suggest an influence of hormonal factors in the occurrence and progression of the disease26,12. Overall, androgens have an immunosuppressive role whereas oestrogens are known to stimulate the immune system. In pregnant women corticotrophin releasing hormone directly stimulates the production of dehydroepiandrosterone, the major androgen in women, by foetal adrenal cells27 and could be the reason for disease remission during pregnancy. In a similar way, oral contraceptives reduce disease severity28 or could even protect against its development29,30. Moreover, during pregnancy, alloantibodies developed against the paternal HLA are found in maternal circulation. These alloantibodies block the function of HLA-DR epitopes and could thus down-regulate the disease31,32. However, the positive effects of pregnancy on RA revert in the post-partum period7.
3.5. Infectious Agents:
Several different infectious agents (e.g. retroviruses, parvoviruses, mycobacteria, borrelia, mycoplasma) have been studied as possible ‘initiators’ of RA, however Epstein-Barr virus is currently the most investigated such agent33,34,5. This virus shares some homologous HLA-DRβ chain epitopes with type-2 collagen. Joint cartilage is rich in this type of collagen and autoimmunity to it can be demonstrated in most RA patients. It is thus suggested that initial infection with Epstein-Barr virus causes a normal immunological reaction. Due to the similarities of the virus with type-2 collagen, the reaction crosses over to affect joint cartilage35. A similar hypothesis exists for Mycobacterium tuberculosis. This bacterium produces a number of heat shock proteins, which have up to 65% sequence homology with human heat shock proteins36. It is suggested that antibodies and T-cells recognize epitopes shared by such proteins of both the infectious agent and the host, facilitating cross-reactivity and triggering an autoimmune response12.
3.6. Other Risk Factors:
Smoking has also been implicated in the initiation of the disease. Its effects appear to be dose depended and heavy smoking associates with increased risk for seropositive disease abnormal rheumatoid factor37. Furthermore, smoking has been suggested to affect severity and outcome of RA38 but findings in other studies are not consistent39. Diet is yet another potential risk factor for the development of RA40.Recent studies have indicated that consumption of fish, olive oil and vegetables could protect against initiation of RA41. Similarly, the increased intake of such food and a concomitant reduction in fat intake can decrease disease severity42. The protective role of fish and vegetable consumption has been attributed to the effect of omega-3 long chain poly unsaturated fatty acids and other anti-oxidants against the oxidative stress associated with rheumatoid arthritis7. The ethnicity can also affect the development of RA. Genetic variations in the rheumatoid epitope and its associations with the progression of the disease have been found in different populations43. This variation in combination with environmental and lifestyle factors e.g. diet are most probably responsible for the geographic variation of the disease7.
Even though our understanding of the aetiology of RA is limited, the pathogenesis of this disease is much clearer. As described previously, an antigen with similar characteristics to a normal cell in the joint triggers an autoimmune reaction which is responsible for the chronic destructive nature of RA40. MHC class II molecules, carrying the antigen, cause naive T cells to divide and differentiate. Activated T cells release a number of bioactive molecules called cytokines. Angiogenic cytokines, such as vascular endothelial growth factor, are responsible for the growth of new blood vessels44 as well as rendering them hyper-permeable45,46 the adhesion of leukocytes mainly CD4+ helper T cells, B-cells and macrophages to the endothelium is initially controlled by E-selection, an adhesion molecule that forms low-affinity bonds with the leukocytes and causes them to slow down and roll along the blood vessel wall47. Migration of these cells to the site of inflammation is then facilitated by other adhesion molecules, such as intercellular adhesion molecules and vascular cell adhesion molecules48. Cytokines, such as TNF-α, IL-1, IL-6, and IL-8, are again implicated in this process by inducing the expression of adhesion molecules on endothelial cells and leukocytes49; penetration of the cartilage by synovial pannus of monomolecular cells and fibroplast50. The main noticeable structural changes are oedema, increased vascularity and hyperplasia of the synovium which manifest clinically as joint swelling and pain12. As the disease progresses, neovascularisation and migration of leukocytes in the synovium continues; hyperplasia of the synovium becomes even more apparent (Henderson et al., 1988). Ultimately, the hypertrophied synovium becomes invasive at the site of the joint where the synovium attaches to the bone or cartilage. This causes the formation of a distinctive tissue, called ‘pannus’ where a high level expression of matrix metalloproteinases is observed insynovial line cells51,52,47. These molecules are involved in the destruction of extracellular matrix and are responsible for the joint erosions observed in RA12,47. Cytokines, especially TNF-α and IL-1 are known to induce their production.
4.1. Cytokines in arthritis:
The pathogenesis of RA as described above is a complicated procedure involving several different mechanisms. However, in every step of the mechanism involvement of cytokines is apparent. Cytokines are a category of soluble proteins that serve as chemical messengers between cells53.They are produced de novo in response to an immune stimulus by a wide variety of cells and can have autocrine, paracrine and endocrine effects. Different cell types can produce the same cytokine or a single cytokine can act on several l different cells i.e. pleiotropy. Several different cytokines can have a similar effect and they can be produced in a cascade finally, cytokines can act synergistically or antagonistically54. Cytokines are involved in several processes including cell growth and differentiation, inflammation, tissue repair, remodelling, and are thus critical to the development and functioning of both the innate and humoral immune responses12. In the rheumatoid synovium the cytokines most often encountered are TNFα, IL-1 and IL-6. Synergistically, TNFα and IL-1 promote a pro-inflammatory profile which induces the functions previously described, namely. T-cells and B-cell recruitment and activation, angiogenesis, chemotaxis, vessel permeability and matrix metalloproteinase production55. TNFα is responsible to a greater extent for the proliferative and inflammatory aspects of the disease, whereas IL-1 is for its destructive aspects12. IL-6 seems to be implicated more in the systemic effects of RA. The sources, functions and effects of cytokines implicated in RA are presented in Table 1
4.2. Systemic Effects of Cytokines:
The effects of cytokines are not limited within the synovium. The local inflammation of RA soon triggers a systemic response of the innate immune system. This response provides an early defense and enables the body to recognize foreign substances early in the infection process prior to the full activation and implementation of the immune responses56. It is characterized by leukocytosis, fever, alterations in the metabolism of many organs as well as changes in the plasma concentrations of various acute phase proteins57. Blood-borne cytokines, especially IL-6, that leave the synovium, reach the liver and stimulate hepatocytes to synthesize and secrete acute phase proteins i.e. soluble pattern recognition receptors that bind onto the pathogen and present it to the respective leukocytes20. Acute phase proteins have been defined as any protein whose plasma concentrations increases or decreases by at least 25% during an acute inflammatory disorder. Acute phase response is normally terminated when the pathogen is eliminated. Mechanisms, involving production of anti-inflammatory cytokines such as IL-10 by Kupffer cells, suppress the expression of IL-6 in the liver and terminate the inflammatory cascade58. However, in chronic or recurring inflammation acute phase response is constantly activated and increasing significantly the levels of acute phase proteins in the blood. An important acute phase protein, for RA, is C-reactive protein (CRP). Its levels, normally below 1 mg.L‑1 of whole blood, can raise 10,000-fold following infection within very short periods of time59. CRP is a prominent indicator of disease activity in RA as well as other conditions. Increased levels of CRP indicate uncontrolled disease or a flare while reduced levels indicate disease remission60. However, most RA patients constantly exhibit CRP levels well above the ‘accepted’ values (i.e. 8mg.L-1)61. Apart from its association with disease activity, CRP has been identified as an independent risk factor for the development of CVD62 and inflammation overall is thought to affect the function and health of several different organs and tissues in the body.
4.3. Transcription Factors:
The way cytokines influence all these functions is by affecting gene transcription. In the process of transcription, RNA is produced from the DNA and this conversion is an essential element in gene expression. The central role of transcription in the process of gene expression means that it regulates the expression of genes in particular cell types or in response to a particular stimuli, such as cytokines. To date two such factors have been implicated in the pathogenesis of RA; the nuclear factor kappa beta (NF-κB) and the activator protein one (AP-1). NF-κB proteins are a family of ubiquitously expressed transcription factors that play an essential role in most immune and inflammatory responses. The NF-κB proteins are retained in an inactive form in the cytoplasm through their interaction with inhibitor of NF-κB proteins63. Stimulation by cytokines, such as TNFα and IL-1, phosphorylates the inhibitor proteins and leads to their ubiquitination and subsequent proteosomal degradation. This enables NF-κB to translocate to the nucleus and stimulate the transcription of genes. Among the numerous genes that NF-κB influences are those of cytokines (TNFα, IL-1and IL-6), adhesion molecules, matrix metalloproteinases and others that control apoptosis and cell proliferation. The NF-κB proteins are highly expressed and activated in the RA synovium64. The increased cellularity of the synovium is a result of the increased recruitment of leukocytes. However, it is also mediated by deficient or even impaired apoptosis resulting from the up-regulation of anti-apoptotic molecules by NF-κB65. Apart from this association with the inhibition of programmed cell death, NF-kB also has an important role in the development and homeostasis of the immune, hepatic, and nervous systems. AP-1 transduces extracellular signals to immune cells, resulting in changes in the expression of specific target genes with an AP-1 binding sites in their promoter or enhancer regions. Even though the knowledge around this transcription factor is relatively limited, several mechanisms by which it may affect the severity of inflammation have been proposed. AP-1 has been suggested to activate cytokine production in co-operation with other transcription factors, regulate differentiation of naive T cells into Th-1 or Th-2 cells or interact and suppress the glucocorticoid receptors63.
5.1. Genetic relevance to arthritis:
The results of several studies have shown a higher disease concordance among monozygotic twins (12–15%) than dizygotic twins (4%), implying the influence of genetic factors66,67.Heritability analysis of these studies suggests that about 60% of a population’s predisposition to rheumatoid arthritis can be accounted for by genetic factors68,69. Analysis of genetic markers has revealed an association between development of rheumatoid arthritis and the presence of a shared epitope on small regions of the DRB1*0401and *0404 alleles70,71. These analyses have also suggested that certain HLA alleles correlate with features of worse disease such as rheumatoid factor, nodules, and erosion72; rapid advances in genetic methods also hold promise for identification of non-HLA disease-association genes73
5.2. Histological changes:
An inflamed synovium is central to the pathophysiology of rheumatoid arthritis. It is histological striking, showing pronounced angiogenesis; cellular hyperplasia, an influx of inflammatory leucocytes and changes in the expression of cell-surface adhesion molecules, proteinases, proteinase inhibitors, and many cytokines. Synovial changes in rheumatoid arthritis vary with disease progression. In the first weeks of the disease, tissue oedema and fibrin deposition are prominent and can manifest clinically as joint swelling and pain. Within a short period, the synovial lining becomes hyperplastic, commonly becoming ten or more cells deep and consisting of type A (macrophage-like) and type B (fibroblast-like) synoviocytes. The sublining also undergoes striking alterations in cellular number and content, with prominent infiltration of mononuclear cells including T cells, B cells, macrophages, and plasma cells. Synovial-vessel endothelial cells transform into high endothelial venules early in the course of the disease74. High endothelial venules are specialised post-capillary venules found in secondary lymphoid tissue or inflamed non-lymphoid tissues; they facilitate the transit of leucocytes from the bloodstream into tissues. The formation of locally invasive synovial tissue known as pannus is a characteristic feature of rheumatoid arthritis. This tissue is involved in the joint erosions seen in rheumatoid arthritis. Pannus is histologically distinct from other regions of the synovium and shows phases of progression. Initially, there is penetration of the cartilage by synovial pannus composed of mononuclear cells and fibroblasts with high-level expression of matrix metalloproteinases by synovial lining cells75,76.
In later phases of the disease, cellular pannus can be replaced by fibrous pannus comprised of a minimally vascularised layer of pannus cells and collagen overlying cartilage77. The tissue derivation of pannus cells has not been fully elucidated, although they are thought to arise from fibroblast-like cells. In-vitro work shows that these fibroblast-like synoviocytes have anchorage-independent proliferation and loss of contact inhibition78 which are phenotypes shown by transformed cells. However, the molecular pathogenic mechanisms driving pannus formation remain poorly understood.
Enlarged image of synovium highlights type A (macrophage-like) and type B (fibroblast-like) composition of lining layer. Sublining shows leucocyte infiltrate and high endothelial venules with increased adhesion-molecule expression facilitating recruitment of leucocytes to inflamed synovium. Erosive interface between pannus and cartilage/bone is shown with high level expression of matrix metalloproteinases.
5.3. T cells:
Several lines of evidence implicate the participation of T cells in the pathogenesis of rheumatoid arthritis. T cells account for part of the mononuclear infiltrate in the synovial sublining, and with slight differences, these lymphocytes can organize into aggregates similar to those found in lymph nodes and Peyer’s patches79The genetic evidence implicating HLA-DR (MHC class II) alleles also suggests a role for T lymphocytes. CD4 T-cell specificity is mediated by interaction of a specific T-cell receptor with a peptide presented by an MHC class II molecule. Thus, the predilection for HLA-DR alleles in rheumatoid arthritis suggests a pathogenic process either at the level of antigen presentation by the MHC molecule or at the level of MHC plus antigen recognition by CD4 T cells. To delineate further the restricting elements defining potential auto reactive Tcell clones, precise use of T-cell-receptor chains in rheumatoid arthritis has been defined in synovial and peripheral T cells. Although these studies suggest overrepresentation of certain receptor chains, they also document heterogeneous receptor populations in the inflamed synovium, arguing against a single pathogenic T-cell-receptor allele80,81 analysis of peripheral T-cell homoeostasis in populations of patients with rheumatoid arthritis shows decreased general diversity of T-cell-receptor use, specific changes in receptor selection, and clonal outgrowth of subsets of CD4 cells82 Thus, one hypothesis for rheumatoid arthritis pathogenesis is aberrant systemic selection or activation of T cells via MHC class II alleles interacting with several T-cell receptors of limited diversity.
The molecular bases underlying the synovial predilection for disease activity remain unknown. Despite the evidence implicating T cells in the pathogenesis of rheumatoid arthritis, other evidence suggests that T cells do not directly cause synovitis in the joint microenvironment. Analysis of synovial infiltrating T cells does not show much proliferation of this population83. Furthermore, comparison of CD45 isoforms in synovial T cells with peripheral blood T cells reveals an enrichment of cells expressing CD45 isoforms characteristic of memory T cells in the rheumatoid arthritis synovium84,85. This phenotype suggests recruitment of previously stimulated and mature T cells as opposed to in-situ maturation of these cells. Finally, by contrast with known T-cell dependent inflammatory processes, analysis of synovial T-cell lymphokine production has shown a small T-cell contribution to cytokine profiles86. Thus, although T cells probably play a part in the systemic initiation of the processes in rheumatoid arthritis, their direct role in synovitis and joint destruction is unclear.
TNF-tumour necrosis factor. Black arrows indicate up regulatory effects, red arrows indicate down regulatory effects. Red crosses represent pathways blocked by anti-TNF drugs.
Other inflammatory mediators: Many other families of inflammatory mediators are active in the synovitis of rheumatoid arthritis; however, their role in the pathogenesis of the disease is less clear. The synthesis of cyclo-oxygenases, nitric oxide synthesis, and neutral proteases is increased in inflammatory synovitis, and these enzymes might mediate parts of the disease process.
Early and effective interventions can minimize the destructive course of RA, thus prompt identification of individuals with RA is essential. Unfortunately, the differential diagnosis of polyarthritis is extensive and includes conditions such as inflammatory bowel disease, psoriatic arthritis, acute rheumatic fever, human-immunodeficiency-viral infection, gout, hyper and hypothyroidism, systemic lupus erythematosus, malignancy and several other. Thus a careful examination of patient’s history, persistence of symptoms, laboratory and radiographic features are essential to establish an accurate diagnosis5. In 1987, the American Rheumatism Association (now known as American College of Rheumatology - ARC) devised a number of criteria for the identification of patients with RA. The full list of these criteria is presented in At least four of the seven criteria have to be present for a patient to be diagnosed with RA (criteria 1-4 for at least six weeks). These criteria can distinguish RA from other forms of arthritis with a specificity of 89% and a sensitivity of 94%87.
Identification arthritis using revised criteria for the classification of rheumatoid arthritis. The 1987 American College of Rheumatology source (Arnett et al., 1988). However, several different medical approaches are used to treat arthritis. The main aims of the treatments are to relieve symptoms joint pain, swelling and stiffness or to decelerate the progression of joint damage88,89. The choice of medication depends on the severity of the disease and its symptoms as well as the response of the patient. The most commonly used medicines for the treatment of arthritis are described below.
7.1. Analgesics: the analgesic is used to relieve the pain relief rather than reduction of inflammation in arthritis. The most commonly prescribed analgesic is paracetamol. Codeine is another analgesic, which is sometimes prescribed as combination with paracetamol or aspirin to obtain additive effect.
7.2. Non-steroidal anti-inflammatory drugs (NSAIDs): Several different types of NSAIDssuch as Ibuprofen and aspirin arefor the treatment of arthritis. In addition, Diclofenac, fenoprofen and flurbiprofen are also frequently prescribed. A new type of NSAIDs, called COX-2 (cyclooxigenase-2) inhibitors is also available. Like analgesics, NSAIDs help to relieve pain while they can also reduce stiffness and inflammation. However, they don’t affect disease progression. Although NSAIDs effective in arthritis ex Cox-2 inhibitors. When they taken in high doses, or over a long period of time, it cause complications, such as digestive problems, stomach bleeding, kidney and liver damage, tinnitus and high blood pressure. COX-2 inhibitors at low dose are generally less harmful to the stomach; however they might increase CVD risk90.
7.3. Corticosteroids: Drugs such as prednisone and methylprednisolone are used to reduce pain, inflammation and can also reduce joint damage91. These drugs are usually used when NSAIDs fail to relieve symptoms92 standard drugs are prescribed on a short term basis, most often during a flare-up. Relief is rapid and the effect can last from a few weeks to several months depending on the severity of the disease. Such drugs act directly on the immune system and lower its response to the antigen93. However, this has a significant impact on the ability of the body to fend off harmful agents such as viruses and bacteria94. Other side effects of corticosteroids include weight gain, osteoporosis, easy bruising, muscle weakness, and thinning of the skin. They can also worsen diabetes and glaucoma and increase risk for CVD95.
7.4. Disease modifying anti-rheumatic drugs (DMARDs): DMARDs are the second line of defense against RA. They were initially prescribed when the above options failed to produce sufficient results; nowadays however they are used earlier in the course of the disease96. While NSAIDs focus on reduction of symptoms, DMARDs aim to reduce the destructive effect of inflammation on the joints. A drawback of these drugs is that it may take several months before their action is noticed, thus early intervention is imperative. Depending on the specific medicine the mechanism of action differs; however, all focus on limitation of the damage caused by inflammation to the bones, tendons, ligaments and cartilage of the joint97. The most commonly prescribed DMARDs at present include methotrexate, sulfasalazine, hydroxychloroquine and leflunomide and can be prescribed either alone or in combination with each other; older drugs, such as gold injections and penicillamine are now rarely used.
7.5. Biologics: the arthritis and tumors necrosis factor alpha (TNFα) blockers are a more recent type of DMARD that act faster compared to other DMARDs. The most commonly prescribed biological include infliximab98, etanercept99,100. TNF-α blockers can usually reduce symptoms within a few weeks and can also slow down or even stop the progression of RA101. TNF-α blockers bind TNF-α in the joint as well as the circulation and prevent its interaction with the cells it targets. This leads to significant reductions in circulating TNF-α and most importantly to rapid relief of symptoms as well as minimizing the effects of RA on the joints102. However, TNF-α blockers may have serious side-effects. They can cause heart failure, infection and lymphoma amongst others. IL-1 and IL -6 blockers are also available. Anakinra blocks the biologic activity of naturally occurring IL-1, improving inflammation and cartilage degradation associated with RA, by competitively inhibiting the binding of IL-1 to the IL-1 type receptor. Even though it is safer compared to TNF-α blockers, it is not as effective in preventing joint damage103. MRA is an anti-IL-6 receptor monoclonal antibody that acts by blocking the activity of IL-6. It has been shown to effectively reduce inflammation and minimize joint damage in RA patients. However, it is a very new drug and its long-term side effects have not yet been extensively studied104,105.
7.6. Surgery: In severe cases of RA, arthroplasty or osteotomy is sometimes required. Its main aim is to restore movement and function of the joint106. Most commonly operated joints are the hips and knees. In the hands most surgeries aim to repair damaged tendons107.
8.7. Imaging studies:
8.1. Plain X – ray: Plain radiography of affected joints is essential in the evaluation of patients. The earliest changes occur in the wrists or feet and consist of soft-tissue swelling and juxta-articular demineralization. Later, the diagnostic changes of uniform joint-space narrowing are evident, and erosions develop. The erosions are often first evident at the fifth metatarsal head or ulnar styloid and at the juxta-articular margins, where the bony surface is not protected by cartilage. These changes frequently take several years to develop.
Currently, magnetic resonance imaging is the best imaging modality to detect erosions. Specially designed magnetic resonance imaging (MRI) equipment called extremity MRI depicts soft-tissue changes and damage to cartilage and bone even better and at an earlier stage than does computed tomography. However, its cost precludes its widespread use.
Special ultrasound techniques called power Doppler ultrasonography (PDUS) or quantitative ultrasound (QUS) may be helpful in RA. Doppler ultrasound can aid in the initial diagnosis of RA even in the presence of minimal radiographic data on presentation. PDUS may be reliable for monitoring inflammatory activity in the joint. QUS, which is used for osteoporosis, has been used to detect bone loss in fingers, which may prove to be a good indicator of early RA. US is a sensitive method for assessing joint inflammatory activity but because it is a very new imaging modality in rheumatology, it is very operator dependent therefore is not a universally clinically relevant imaging tool for RA at this time. Doppler ultrasound is currently utilized by few rheumatologists in the academic setting, to follow up on patients with inflammatory arthritis L.108, 109
Rheumatoid arthritis (RA) is a chronic systemic inflammatory polyarthritis of unknown etiology. In addition to the joint manifestations, RA is an illness, which affects most organ systems with significant morbidity and mortality. However, the new medications and treatment regimens may decrease the observed morbidity and mortality from this disease.
1. Barnes CG and Mason M. Rheumatoid arthritis. In Introduction to Clinical Rheumatology (Edited by Mason M. and Currey HLF), Chap. 2. Pitman, Bath, 1975.
2. Mottonen TT. Prediction of erosiveness and rate of development of new erosions in early rheumatoid arthritis. Ann Rheum Dis 1988; 47: 648–653.
3. Van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol 1995; 34 (supplement 8).
4. Onions CT, Friedrichsen GWS and Burchfield RW. (1996). The Oxford Dictionary of English Etymology. Oxford University Press, Oxford, UK.
5. Hunder GG. 2005. Atlas of rheumatology. Current Medicine, Philadelphia, USA.
6. Land ré Beauvais, A. J. (2001). The first description of rheumatoid arthritis.Unabridged text of the doctoral dissertation presented in 1800. Joint bone spine. 68, 130-43.
7. Alamanos Y and Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev. 2005; 4: 130-6.
8. Shichikawa K, Inoue K, Hirota S, Maeda A, Ota H, Kimura M, Ushiyama T and Tsujimoto M. Changes in the incidence and prevalence of rheumatoid arthritis in Kamitonda, Wakayama, Japan, 1965-1996. Ann Rheum Dis. 1999; 58: 751-6.
9. Guillemin F, Briancon S, Klein JM, Sauleau E and Pourel J. Low incidence of rheumatoid arthritis in France. Scand J Rheumatol. 1994; 23: 264-8.
10. Erhardt CC, Mumford PA, Venables PJ and Maini R N. Factors predicting a poor life prognosis in rheumatoid arthritis: an eight year Prospective study. Ann Rheum Dis. 1989; 48: 7-13.
11. Glennas A, Kvien TK, Andrup O, Karstensen B and Munthe E. Recent onset arthritis in the elderly: a 5 year longitudinal observational study. J Rheumatol. 2000; 27: 101-8.
12. Buch M and Emery P. The aetiology and pathogenesis of rheumatoid arthritis. Hospital Pharmacist. 2002; 9: 5-10.
13. Gabriel S E, Crowson CS and O'Fallon WM. The epidemiology of rheumatoid arthritis in Rochester, Minnesota, 1955-1985. Arthritis Rheum. 1999; 42: 4115-20.
14. Simonsson M, Bergman S, Jacobsson LT, Petersson IF, Svensson B. The prevalence of rheumatoid arthritis in Sweden. Scand J Rheumatol 1999; 28: 340–3.
15. Symmons D, Turner G, Webb R, Asten P, Barrett E, Lunt M et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology 2002; 41: 793–800.
16. Lisa K. Stamp, Michael J. James and Leslie G. Cleland. Diet and Rheumatoid. Loeser JD, Melzack R.(1999). Pain: an overview. Lancet. 2005; 353: 1607–9.
17. Melzack R. and Wall PD. The Challenge of Pain. Penguin, Harmondsworth, 1982.
18. Maya Buch and Paul Emery. The aetiology and pathogenisis of rheumatoid arthritis. J. Hospi Pharmacist. 9; 5-10.
19. Jarvinen P and Aho K. Twin studies in rheumatic diseases. Semin Arthritis Rheum. 1994; 24: 19-28.
20. Cotran RS, Kumar V and Collins T. (1999). Pathologic basis of disease. W.B. Saunders Company, Philadelphia, USA.
21. Ollier WE and MacGregor A. Genetic epidemiology of rheumatoid disease. Br Med Bull 1995; 51: 267–85.
22. Hajeer AH, Dababneh A, Makki RF, Thomson W, Poulton K, Gonzalez- Gay MA, Garcia-Porrua C, Mattey DL and Ollier WE. (2000). Different gene loci within the HLA-DR and TNF regions are independently associated with susceptibility and severity in Spanish rheumatoid arthritis patients. Tissue Antigens. 55, 319-25.
23. Silman AJ, MacGregor AJ, Thomson W, et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 1993; 32: 903–07.
24. H. Mu, et al., and Tumor necrosis factor a microsatellite polymorphism is associated with rheumatoid arthritis severity through an interaction with the HLA-DRB1 shared epitope, Arthritis Rheum. 1999; 42(3): 438–442.
25. Shiozawa S, Shiozawa K and Fujita T. Morphologic observations in the early phase of the cartilage-pannus junction: light and electron microscopic studies of active cellular pannus. Arthritis Rheum 1983; 26: 472–78.
26. Hazes, J. M. and Van Zeben, D. Oral contraception and its possible protection against rheumatoid arthritis. Ann Rheum Dis. 1991; 50: 72-4.
27. Smith R, Mesiano S, Chan EC, Brown S and Jaffe RB. Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells. J Clin Endocrinol Metab. 1998; 83: 2916-20.
28. Van Zeben, D., Hazes, J. M., Vandenbroucke, J. (1990). Diminished incidence of severerheumatoid arthritis associated with oral contraceotive use. Arthritis Rheum. 33, 1462-5.
29. Haze s, J. M. and van Zeb en, D. (1991). Oral contraception and its possible protection against rheumatoid arthritis. Ann Rheum Dis. 50, 72-4.
30. Koepsell TD, Dugowson CE, Nelson JL, Voigt LF and Daling JR. Non-contraceptive hormones and the risk of rheumatoid arthritis in menopausal women. Int J Epidemiol. 1994; 23: 1248-55.
31. Moynier M, Cosso B, Brochier J and Clot J. Identification of class II HLA alloantibodies in placenta-eluted gamma globulins used for treating rheumatoid arthritis. Arthritis Rheum. 1987; 30: 375-81.
32. Kim GY, Kim SH, Hwang SY, Kim HY, Park YM, Park SK, Lee MK, Lee SH, Lee TH. and Lee JD. Oral administration of proteoglycan isolated from Phellinus linteus in the prevention and treatment of collagen-induced arthritis in mice. Biol Pharm Bull. 2003; 26: 823-31.
33. Krause A, Kamradt T and Burmester GR. Potential infectious agents in the induction of arthritides. Curr Opin Rheumatol. 1996; 8: 203-9.
34. Schaeverbeke T, Vernhes JP, Lequen L, Bannwarth B, Bebear C and Dehais J. Mycoplasmas and arthritides. Rev Rhum Engl Ed. 1997; 64: 120-8.
35. Cotran RS, Kumar V and Collins T. (1999). Pathologic basis of disease. W.B. Saunders Company, Philadelphia, USA.
36. Kaufmann SH. Heat-shock proteins: a link between rheumatoid arthritis and infection? Curr Opin Rheumatol. 1990; 2: 430-5.
37. Wilson K and Goldsmith CH. Does smoking cause rheumatoid arthritis? J Rheumatol. 1999; 26: 1-3.
38. Manfredsdottir, V. F., Vikingsdottir, T., Jonsson, T., Geirsson, A. J., Kjartansson, O., Heimisdo ttir, M., Sigurdardottir, S. L., Valdimarsson, H. and Vikingsson A. (2006). The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology (Oxford). 45, 734-40.
39. Finckh, A., Dehler, S., Costenbader, K. H., Gabay, C. and on behalf of the Swiss Clinical Quality Management project for RA (SCQM) (2007). Cigarette smoking and radiographic progression in rheumatoid arthritis. Ann RheumDis. 66, 1066-71.
40. Lisa K. Stamp, Michael J. James and Leslie G. Cleland. Diet and Rheumatoid. Loeser JD, Melzack R.(1999). Pain: an overview. Lancet. 2005; 353: 1607–9.
41. Cleland, L. G., James, M. J. and Proudman, S. M. (2003). The role of fish oils in the treatment of rheumatoid arthritis. Drugs. 63, 845-53.
42. Cleland L G and James M J. The role of fats in the lifecycle stages. Adulthood--prevention: Rheumatoid Arthritis. Med J Aust. 2002; 17: S119- 20.
43. Drosos AA, Alamanos I, Voulgari PV, Psychos DN, Katsaraki A, Papadopoulos I, et al. Epidemiology of adult rheumatoid arthritis in northwest Greece 1987–1995. J Rheumatol 1997; 24: 2129– 33.
44. Fearon, U., Griosios, K., Fraser, A., Reece, R., Emery, P., Jones, P. F. and Veale,D. J. (2003). Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol. 30, 260-8.
45. Ferraa CM, Kumar M, Nicklas B, McCrone S and Goldberg AP. Weight gain and adipose tissue metabolism after smoking cessation in women. Int J Obes Relat Metab Disord. 200; 25: 1322-6.
46. Malemud CJ. Growth hormone, VEGF and FGF: involvement in rheumatoid arthritis. Clin Chim Acta. 2007; 375: 10-9.
47. Ospelt C and Gay S. The role of resident synovial cells in destructive arthritis. Best Pract Res Clin Rheumatol. 2008; 22: 239-52.
48. Malik A and Lo S. Vascular endothelial adhesion molecules and tissue inflammation. Pharmacol Rev. 1996; 48: 213-29.
49. Nassonov EL, Samsonov MY, Chichasova NV, Nikiphorova EL, Tilz GP, Demel U, Widner B and Fuchs D. Soluble adhesion molecules in rheumatoid arthritis. Rheumatology. 2000; 39; 808-10.
50. Shiozawa S, Shiozawa K and Fujita T. Morphologic observations in the early phase of the cartilage-pannus junction: light and electron microscopic studies of active cellular pannus. Arthritis Rheum 1983; 26: 472–78.
51. McCachren SS, Haynes BF and Niedel JE. Localization of collagenase mRNA in rheumatoid arthritis synovium by in situ hybridization histochemistry. J Clin Immunol 1990; 10: 19–27.
52. Gravallese EM, Darling JM, Ladd AL, Katz JN, Glimcher LH. In situ hybridization studies of stromelysin and collagenase messenger RNA expression in rheumatoid synovium. Arthritis Rheum 1991; 34: 1076–84.
53. David M Lee, Michael E and Weinblatt. Review of rheumatoid arthritis. J. Lancet 2001; 358: 903–11.
54. Ashman R and Papadimes in Bhag Bland Bolan A itriou J. Production and function of cytokine natural and acquired immunity to Candida albicans infection. Microbiol. Rev. 1995; 59: 646-72.
55. Klimiuk PA, Goronzy JJ, Bjor nsson J, Beckenbaugh RD and Weyand CM. Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am J Pathol. 151, 1311-9.
56. Baumann H and Gauldie J. The acute phase response. Immunol Today. 1994; 15: 74-80.
57. Gabay C and Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999; 340: 448-54.
58. Suffredini AF, Fantuzzi G, Badolato R, Oppenheim JJ and O'Grady NP. New insights into the biology of the acute phase response. J Clin Immunol. 1999; 19: 203-14.
59. Pepys MB and Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003; 111: 1805-12.
60. Crockson AP, Crockson RA and Mcconkey B. C-reactive protein in rheumatoid arthritis. Arthritis and Rheumatism. 1978; 21: 491.
61. Kushner I. C-reactive protein in rheumatology. Arthritis and Rheumatism. 1991; 34: 1065-8.
62. Ridker PM, Rifai N, Rose L, Buring JE and Cook NR. Comparison of C - reactive protein and Low-Density Lipoprotein Cholesterol Levels in the Prediction of First Cardiovascular Events. NEJM. 2002; 347: 1557-65.
63. Miagkov AV, Kovalenko DV, Brown CE, Didsbury JR, Cogswell JP, Stimpson SA, Baldwin AS and Makarov SS. NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Natl Acad Sci U S A. 1998; 95: 13859-64.
64. Perlman H, Liu H, Georganas C, Koch AE, Shamiyeh E, Haines GK and Pope RM. Differential expression pattern of the antiapoptotic proteins, Bcl-2 and FLIP, in experimental arthritis. Arthritis and Rheumatism. 2001; 44: 2899-908.
65. Okamoto H, Cujec TP, Yamanaka H and Kamatani N. (2008). Molecular aspects of rheumatoid arthritis: role of transcription factors. Febs J. Makarov, S. S. (2001). NF-kappa B in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res. 3, 200-6.
66. Aho K, Koskenvuo M, Tuominen J, Kaprio J. Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol 1986; 13: 899-902.
67. Silman AJ, MacGregor AJ, Thomson W, et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 1993; 32: 903–07.
68. MacGregor AJ, Snieder H, Rigby AS, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 2000; 43: 30–37.
69. MacGregor AJ and Silman AJ. Rheumatoid arthritis and other synovial disorders: classification and epidemiology. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatology, 3rd ed. Mosby. p. 757– 63.
70. Wordsworth BP, Lanchbury JS, Sakkas LI, Welsh KI, Panayi GS, Bell JI. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci USA 1989; 86: 10049–53.
71. Ronningen KS, Spurkland A, Egeland T, et al. Rheumatoid arthritis may be primarily associated with HLA-DR4 molecules sharing a particular sequence at residues 67–74. Tissue Antigens 1990; 36: 235–40.
72. Ollier WE and MacGregor A. Genetic epidemiology of rheumatoid disease. Br Med Bull 1995; 51: 267–85.
73. Seldin MF, Amos CI, Ward R and Gregersen PK. The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum. 1999; 42: 1071–79.
74. Girard JP, Springer TA. High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol Today 1995; 16: 449–57.
75. McCachren SS, Haynes BF and Niedel JE. Localization of collagenase mRNA in rheumatoid arthritis synovium by in situ hybridization histochemistry. J Clin Immunol 1990; 10: 19–27.
76. Gravallese EM, Darling JM, Ladd AL, Katz JN, Glimcher LH. In situ hybridization studies of stromelysin and collagenase messenger RNA expression in rheumatoid synovium. Arthritis Rheum 1991; 34: 1076–84.
77. Kobayashi I, Ziff M. Electron microscopic studies of the cartilage pannus junction in rheumatoid arthritis. Arthritis Rheum. 1997; 18: 475–83.
78. Lafyatis R, Remmers EF, Roberts AB, Yocum DE, Sporn MB, Wilder RL. Anchorage-independent growth of synoviocytes from arthritic and normal joints: stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids. J Clin Invest 1989; 83: 1267–76.
79. Rooney M, Whelan A, Feighery C, Bresnihan B. The immunohistologic features of synovitis, disease activity and in vitro IgM rheumatoid factor synthesis by blood mononuclear cells in rheumatoid arthritis. J Rheumatol 1989; 16: 459–67.
80. Jenkins RN, Nikaein A, Zimmermann A, Meek K and Lipsky PE. T cell receptor V beta gene bias in rheumatoid arthritis. J Clin Invest 1993; 92: 2688–701.
81. Uematsu Y, Wege H, Straus A, et al. The T-cell-receptor repertoire in the synovial fluid of a patient with rheumatoid arthritis is polyclonal. Proc Natl Acad Sci USA 1991; 88: 8534–38. Unabridged text of the doctoral dissertation presednted in 1800. Joint Bone USA.
82. Wagner UG, Koetz K, Weyand C and Goronzy JJ. Perturbation of the T cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci USA 1998; 95: 14447–52.
83. Nykanen P, Bergroth V, Raunio P, Nordstrom D and Konttinen YT. Phenotypic characterization of 3H-thymidine incorporating cells in rheumatoid arthritis synovial membrane. Rheumatol Int 1986; 6: 269–71.
84. Kohem CL, Brezinschek RI, Wisbey H, Tortorella C, Lipsky PE, Oppenheimer-Marks N. Enrichment of differentiated CD45RBdim, CD27- memory T cells in the peripheral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 1996; 39: 844–54
85. Koch AE, Robinson PG, Radosevich JA, Pope RM. Distribution of CD45RA and CD45RO T-lymphocyte subsets in rheumatoid arthritis synovial tissue. J Clin Immunol 1990; 10: 192–99.
86. Feldmann M, Brennan FM and Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996; 14: 397–440.
87. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31: 315-24.
88. Mottonen TT. Prediction of erosiveness and rate of development of new erosions in early rheumatoid arthritis. Ann Rheum Dis 1988; 47: 648–653.
89. Van der Heide A, Jacobs JWG, Bijlsma JW et al. The effectiveness of early treatment with ‘second-line’ antirheumatic drugs. A randomized, controlled trial. Ann Intern Med 1996; 124: 699–707.
90. Mukarerjee,D., Nissen, S. E. and Topol, E. J. (2001). Risk of cardiovascular events associated with selective COX-2 inhibitors. Jama. 286, 954-9.
91. Piestsky DS and St Clair EW. Progress in the treatment of rheumatoid arthritis. JAMA. 2001; 286: 2787-90.
92. Verhoeven A, Boers M and Tugwell P. Combination therapy in rheumatoid arthritis: updated systematic review. Rheumatology. 1998; 37: 612-9.
93. Vane J and Botting R. Inflammation and the mechanism of action anti-inflammatory drugs. FASEB J. 1987; 1: 89-96.
94. Doran MF, Pond GR, Crowson CS, OFallon WM and Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum. 2002b; 46: 625-31.
95. Panoulas VF, Douglas KM, Milionis HJ, Stavropoulos-Kalinglou A, Nightingale P, Kita MD, Tselios AL, Metsios GS, Elisaf MS and Kitas GD. Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology (Oxford). 2007; 46: 1477-82.
96. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis: a metaanalysis of published clinical trials. Arthritis Rheum 1992; 35: 1117–25.
97. Kremer JM. Rational Use of New and Existing Disease-Modifying Agents in Rheumatoid Arthritis. Ann Intern Med. 2001; 134: 695-706.
98. Risley S, Thomas MA, and Bray V. Rheumatoid arthritis, new standards of care: nursing implications of infliximab. J Orthopaedic Nursing. 2004; 8(1): 41–49.
99. Weinblatt ME, Kremer JM, Bankhurst A.D., et al., A trial of etanercept, a recombinant tumour necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. NEJM. 1999; 340: 253–259.
100. Klareskog L, Van der Heijde D, De Jager JP, et al., Therapeutic effect of the combination of evanescent and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized controlled trial. Lancet 2004; 363: 675–681.
101. Isenberg D and Morrow J 1995. Friendly Fire: Explaining Autoimmune Disease. Oxford University Press, Oxford.
102. Louie, S., Park, B. and Yoon, H. (2003). Biological response modifiers in the management of rheumatoid arthritis. Am J Health Syst Pharm. 6 0, 346-55.
103. Fleashhmann, RM. (2002). Safety of anakinra, a recombinant interleukin-1 receptor antagonist (r-metHuIL-1ra) in patients with rheumatoid arthritis and comparison to anti-TNF-alpha agents. Clin Exp Rheumatol. 20, S35-41.
104. Choy EHS, Isenberg DA, Garrood T, Farrow S, Ioanno Cheung N, Williams B, et al. Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: A randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis and Rheumatism. 2002; 46: 3143-50.
105. Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J and Kishimoto T. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: A multicenter, double-blind, placebo-controlled trial. Arthritis and Rheumatism. 2004; 50: 1761-9.
106. Coventry MB. Osteotomy about the Knee for Degenerative and Rheumatoid Arthritis: indications, operative technique, and results. J Bone Joint Surg Am. 1973; 55: 23-48.
107. Clayton, M. L. (1965). Surgical Treatment at the Wrist in Rheumatoid Arthritis: A Review of thirty-seven patients. J Bone Joint Surg Am. 47, 741-50.
108. Casimiro L et al. Therapeutic ultrasound for the treatment of rheumatoid arthritis, Cochrane Database Syst. Rev. 2002; 3: CD0037-87.
109. Teh J, et al., Power Doppler ultrasound of rheumatoid synovitis: quantification of therapeutic response, Br. J. Radiol. 2003; 76(12): 875–879.
Received on 10.04.2010 Modified on 13.05.2010
Accepted on 31.05.2010 © RJPT All right reserved