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Author: Elena Massarotti, M.D.
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1. Learning Objectives

  • Identify and describe the synovial features of RA
  • Identify the clinical characteristics of RA and the concept of pattern recognition as it applies to chronic inflammatory arthritis
  • Describe the immunologic mechanisms underlying the pathogenesis of the disease, and how it relates to therapy

2. Introduction

Rheumatoid arthritis (RA) is the most common type of chronic inflammatory arthritis. The other types of chronic inflammatory arthritis you will learn about include Lyme arthritis and the seronegative spondyloarthropathies. These types of chronic inflammatory arthropathies (or arthritides) share common pathologic features within the diseased synovium but have very different clinical manifestations.

3. The Normal Synovium and the RA Synovium

Synovium, the lining of diarthrodial joints, is the tissue initially affected in the various forms of chronic inflammatory arthritis. Normal synovium consists of only two or three layers of lining cells on a stroma of connective tissue. The cellular types have macrophage and fibroblast like features. It is a highly vascular tissue that normally generates small amounts of synovial fluid and probably serves a nourishing and lubrication function for hyaline cartilage. In the various forms of chronic inflammatory arthritis, the synovium is the “target lesion” and the diseased synovium shows villous hypertrophy, surface fibrin deposits, vascular proliferation, lymphoplasmacellular infiltrates, and sometimes pseudolymphoid follicles. The CD4+ T cell is a major infiltrating cell in the synovial lesion in RA and other the other types of chronic inflammatory arthritis, and probably plays a central role in the pathogenesis of these diseases. This diseased synovial tissue is called pannus. This pannus, or hypertrophied synovium, releases proteinases that lead to “erosions’ in the cartilage, and disruption of the periarticular structures (ligaments), which then lead to joint instability.

4. Clinical Patterns of Inflammatory Arthritis

The combination of the history, physical examination, laboratory and radiographic studies best identifies the specific type of arthritis that may be present in a patient. Pattern recognition is an important clinical tool and refers to the number and size of joints involved, and whether the joints are affected in a symmetric or asymmetric fashion. An arthritis may be monoarticular (one joint), oligoarticular (affecting four joints or less but greater than one joint), or polyarticular (affecting greater than four joints). When similar joints on both sides of the body are affected, the arthritis is said to be “symmetric” (i.e. both sets of MCP joints); when two or more different joints are affected on one or both sides, the arthritis is said to be “asymmetric” (i.e. a wrist and a great toe joint). For example, lupus and rheumatoid arthritis are clinically generally characterized by a pattern of symmetric, small, and large joint polyarthritis while bacterial, septic arthritis is usually characterized by a pattern of large joint monoarticular arthritis.

5. Epidemiology of Rheumatoid Arthritis

RA affects 1% of the North American population, and women are affected more than men in a ratio of 3:1. The age of onset is usually between the ages of third and fifth decades, but it can occur early on in life, and in the later years as well. Caucasians are more likely to be affected, and men with high rheumatoid factors may be at risk for more severe disease. Lack of a formal education seems to be a risk factor, more so than lower socioeconomic status. Cigarette smoking may also contribute to disease. A positive family history is a strong risk factor, as is the presence of high amounts of rheumatoid factor (see below), polyarticular disease at presentation and systemic features (fever, weight loss, malaise) at disease onset. There are important genes known to be associated with the development of more aggressive disease: HLADRb1*0402, 0404, and 0408. In addition, the presence of the “shared epitope” (SE), which is a short amino acid sequence found on the beta chain of several HLA DR alleles, is associated with a propensity to develop RA. (see below) It is thought that this shared epitope may be responsible for perpetuating an activated T cells in the diseased synovium.

6. The Arthritis in RA

Since the synovium is the target lesion, joints lined by synovium are affected. The small joints of the hands are particularly affected, including the MCP and PIP joints; the DIP joints tend to be spared. The high cervical spine at C1-2 is affected, with the potential for “pithing” of the spinal cord. (The odontoid is lined by synovium, and forms part of C2; the C1 ring surrounds the odontoid and is reinforced by ligaments; pannus formation at the odontoid can potentially disrupt the C1-C2 articulation, and lead to severing of the spinal cord at this level.) The elbows, knees, hips, ankles and foot joints are also commonly affected. The thoracic and lumbar spines are not typically affected directly by RA since there is very little synovium present in the facet joints of the lumbar and thoracic spines.

7. Extraarticular Manifestations of RA

Patients with RA may have manifestations outside the joints themselves. “Constitutional” symptoms of fever, weight loss, and malaise are not uncommon, and are thought to be due to the proinflammatory cytokines that are triggered by the disease (TNF-á, Il-1, and Il-6). Dryness in the eyes and mouth (sicca complex) can also occur, signifying the presence of secondary Sjogren’s syndrome. (Primary Sjogren’s syndrome is another autoimmune illness characterized by lymphocytic infiltration of exocrine glands; arthritis and vasculitis can also be seen with it.) Nodules, which are rubbery masses over the extensor surfaces and pressure points, are seen with more severe disease and present in about 30% of patients with RA. Pathologically, they are characterized by a central area of necrosis surrounded by palisading fibroblasts that in turn produce metalloproteinases. Lymphocytes within nodules may produce rheumatoid factor and pro-inflammatory cytokines. Other organ systems affected by RA include the cardiovascular system (pericarditis), lungs (pleural effusions) and skin and peripheral nervous system (vasculitis). It should be noted that with the advent of methotrexate and biological therapies (see below) the occurrence of these extrarticular manifestations has waned.

8. Laboratory Features of RA

A normochromic, normocytic anemia may be present, due to diminished erythropoesis seen with acute and chronic inflammatory states. Increased levels of acute phase reactants (ESR, CRP, haptoglobin, ferritin, platelets) is common, and considered a diagnostic marker by the American College of Rheumatology (ACR). Abnormalities in the liver and kidney function tests may occur as a result of medications used to treat RA but disease manifestation within the kidney and liver itself is uncommon.

Over 80% of patients with RA possess measurable levels of rheumatoid factor, usually IgM, which is an antibody directed against the Fc portion of IgG. It is not considered to be diagnostic of RA since it can be found in other inflammatory states (chronic infections like TB and endocarditis) and in diseases where there is polyclonal stimulation of B cells. It is also present in about 15% of the normal population over age 65. It generally does not follow disease activity (the acute phase reactants do follow disease activity). Synovial fluid analysis in RA is characterized by inflammatory joint fluid with white cell counts usually greater than 2000 cells/mm3. The white cells are mostly neutrophils (as opposed to the predominant round cell infiltrate seen in the synovium).

The synovial fluid in RA patients is usually cloudy or yellow (normal synovial fluid is clear). The joints of many patients with RA have palpable effusions, which contain large amounts of synovial fluid produced by the diseased synovium. This synovial fluid can be aspirated, and the joint injected with corticosteroids to help treat symptomatic joints.

9. Diagnosis of RA

RA is diagnosed on clinical grounds. The ACR has devised a set of diagnostic criteria for RA that require the presence of four of the seven following items for a definitive diagnosis of RA to be present: symmetric arthritis (lasting at least 6 weeks), hand synovitis (lasting at least 6 weeks), morning stiffness lasting greater than one hour, presence of acute phase reactants, presence of rheumatoid factor, presence of x-ray abnormalities- specifically erosions, (which represent the infiltration of pannus into hyaline cartilage), and nodules. These criteria are very useful for grouping patients into clinical trials as well.

10. The Pathogenesis of RA

The following pathogenetic framework applies to RA and the chronic inflammatory arthropathies: certain infectious agents in genetically susceptible individuals may induce an untoward immune response with autoreactive features that leads to chronic arthritis. In rheumatoid arthritis, however, there is no convincing data, to date, that infectious agents play a role in the disease. In Lyme arthritis, it is clear that they do. Although the genetic susceptibility to rheumatoid arthritis and probably Lyme arthritis involves multiple genes, similar immunogenetic class II major histocompatibility complex (MHC) molecules are involved in determining the severity of both diseases. One of the leading theories to explain how an infectious agent may induce an autoimmune response is by molecular mimicry between a T cell epitope of the infectious agent and a self-component in the joint.

Support for a genetic predisposition in RA comes from studies that rheumatoid arthritis clusters in families and there is a high concordance of the disease in monozygotic twins. It has been estimated that a first-degree relative of an RA patient has about a 16-fold increased risk of acquiring the disease compared with the general population. Studies of monozygotic twins have shown a concordance rate between 15% to 30%, which is approximately 4 times greater than the rate in dizygotic twins.

Although the severity of rheumatoid arthritis involves multiple genes, the best understood are those that encode class II major histocompatibility complex (MHC) molecules. It has been estimated that MHC alleles may account for approximately 30% of the genetic risk of severe rheumatoid arthritis. The most severe, erosive disease is associated with HLA-DR4 alleles. There are as many as 19 different subtypes of HLA-DR4. Only certain subtypes, called HLA-DRB1*0401, 0404 and 0408, are associated with rheumatoid arthritis, whereas the HLA-DR4*0402 and 0403 subtypes are not associated with this illness. These subtypes differ by only a few amino acid sequences in the third diversity region of the β1 chain of the DR4 molecule (location of the shared epitope). In this way, susceptibility to rheumatoid arthritis was linked to a particular sequence from amino acids 70-74 in the β1 chain. It is now known that this sequence may be found in as many as 15 different alleles, and they are now called rheumatoid arthritis (RA) alleles. The most prominent are called HLA-DRB1*0401/0404 and HLA-DRB1*0101/0102 alleles.

Class II MHC molecules are normally found on B cells and macrophages, but in sites of inflammation, they may also be expressed on other activated cells including T cells, synovial cells and endothelial cells. Foreign antigens are phagocytosed by macrophages that then present peptide fragments of the antigens in association with the MHC product to helper T cells. These T cells only see foreign antigen in association with the MHC product. This is thought to make the development of autoimmune phenomena less likely. Helper T cells may either stimulate cytotoxic T cells or they may stimulate B cells to produce antibody against the foreign antigen. However, to date, no antigens have been identified that clearly have a causal role in rheumatoid arthritis.

Although the etiology of rheumatoid arthritis is not known, a great deal is known about the subsequent inflammatory events that lead to joint destruction. The following discussion is not complete, but includes some of the more important components. Macrophages release large amounts of interleukin-1β (IL-1β) and tumor necrosis factor-? (TNF-?), which are strong pro-inflammatory cytokines that may be important in the development of autoimmune phenomena within the joint. Macrophages also secrete angiogenesis factors that cause increased vascularization of the tissue. T cells are the predominant infiltrating cells in the synovium and most of them carry the CD4+ helper-inducer marker. These cells secrete primarily interferon-γ (IFN-γ), which is also an important pro-inflammatory cytokine.

Although not specific for the disease, the production of autoantibodies (by plasma cells) with specificity for the Fc fragment of IgG (rheumatoid factors) is a major immunologic abnormality in rheumatoid arthritis. In this disease, immune complexes are often found in joint fluid, and these complexes frequently contain IgM and IgG rheumatoid factors, which are directed against self-IgG. Some of the immune complexes bind complement with liberation of C5a, which is chemotactic for polymorphonuclear leukocytes, the predominant cell type in joint fluid. Polymorphonuclear leukocytes may damage tissue within the joint by the release of acid and neutral proteinases and by the generation of free radicals from the reduction of molecular oxygen. These radicals -- superoxide and singlet oxygen -- have the potential to damage lipid membranes, degrade hyaluronic acid, inactivate proteinase inhibitors, and catalyze production of chemotactic lipids. Furthermore, synovial cells release large amounts of collagenase, which degrade collagen. These cells also release prostaglandins and leukotrienes, which are arachadonic acid metabolites that cause vasodilatation and increase vasopermeability. These enzymes eventually damage cartilage and bone that may ultimately lead to the complete destruction of joints.

The identification of these pro-inflammatory cytokines (TNF-á, Il-1 and Il-6) and other important cells involved in the pathogenesis of RA have led to the development of targeted biological therapies that are dramatically changing how RA is being treated. (see below)

11. Treatment Considerations in RA

The major goals of RA treatment are to relieve pain, preserve joint function, and minimize the toxicity from medications and other treatments. Both pharmacologic and nonpharmacologic treatments are used, the latter consisting of physical therapy, occupational therapy, and surgical treatments. Nonsteroidal antinflammatory agents (NSAIDs) form one of the major cornerstones of treatment. They provide symptomatic relief but do not reverse joint damage or prevent joint damage. COX-1 and COX-2 inhibitors are equally effective but have different side effect profiles. (The only COX-2 inhibitor remaining on the market is celecoxib; Merck, the company manufacturing rofecoxib, voluntarily withdrew it and the FDA withdrew valdecoxib.) The major toxicities of NSAIDs include gastrointestinal (gastritis and ulcer formation) and cardiovascular side effects (hypertension, edema, and myocardial infarction.)

12. DMARDS (Disease modifying antirheumatic drugs)

The ACR recommends that all patients with RA be treated with DMARDs within three months of diagnosis. DMARDs have been shown to specifically retard the progression of joint disease. These medications act in different ways to mitigate the inflammatory process. It is not known how hydroxychloroquine abrogates disease manifestations. Methotrexate and leflunomide inhibitor purine and pyrimidine biosynthesis, respectively, and as such lead to decreased inflammation within the synovium.

13. Biological Therapies

These newer treatments, developed by the biotechnology world and available for the last eight years, target specific immune mediated processes. Inhibitors of TNF? include etanercept, infliximab, and adalimumab. Kineret is an antagonist against the IL-1 receptor. The TNFá inhibitors are equally effective in treating RA, and can be used alone or in combination with DMARDs. In development now are two other biological therapies: a monoclonal antibody directed against CD20 (rituximab), found on B cells and thus resulting in B cell depletion, and a fusion protein (abatacept) that selectively modulates the CD80 or CD86–CD28 costimulatory signal required for full T cell activation. CD80 or CD86 on the surface of an antigen-presenting cells binds to CD28 on T cells. The naturally occurring inhibitory molecule, cytotoxic T-lymphocyte antigen 4 (CTLA4), is induced on the surface of the T cell. CTLA4 has a greater affinity for CD80 or CD86 than does CD28. The new fusion protein product, abatacept, like CTLA4, competes with CD28 for CD80 and CD86 binding and selectively modulates T cell activation.

14. Summary

RA is the most common inflammatory arthritis that primarily affects women and is incurable. Its cause remains unknown. Manifestations of disease include organ systems outside the musculoskeletal system. The diagnosis is made with the combination of the history, physical findings, and laboratory and radiographic studies. Multiple modalities are used to treat the disease, and newer treatments have been developed and in development are dramatically changing the prognosis for this disease, for the better.

15. References

  • Harris ED Jr: Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med 1990; 322:1277-1289.
  • Gregersen PK, Shen M, Song QK, et al. Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci 1986; 83:2642-46.
  • Weyand CM, Hicok KC, Conn D, Goronzy JJ: The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med 1995; 177:801-806.
  • Doan T, Massarotti E: Rheumatoid Arthritis: An Overview of New and Emerging Therapies. J Clin Pharm 2005; 45: 751-762.