Rheumatoid Arthritis Pathophysiology
- Histopathology
- Radiology
- Initiation of Disease
- Propagation of Disease
- Rational Approaches to Treatment
- Additional Reading
There are two popular theories regarding the pathogenesis of rheumatoid arthritis (RA). The first holds that the T cell, through interaction with an - as yet unidentified - antigen, is the primary cell responsible for initiating the disease as well as for driving the chronic inflammatory process. This theory is based upon the known association of RA with class II major histocompatability antigens, the large number of CD4+ T cells and skewed T cell receptor gene usage in the RA synovium. The second theory holds that, while T cells may be important in initiating the disease, chronic inflammation is self-perpetuated by macrophages and fibroblasts in a T-cell independent manner. This theory is based upon the relative absence of activated T cells phenotypes in chronic RA and the preponderance of activated macrophage and fibroblast phenotypes.
Synovium Cartilage Bone Synovial Cavity
Synovium
The synovium, in normal joints, is a thin delicate lining that serves several important functions.
The synovium serves as an important source of nutrients for cartilage since cartilage itself is avascular. In addition, synovial cells synthesize joint lubricants such as hyaluronic acid, as well as collagens and fibronectin that constitute the structural framework of the synovial interstitium.
1. Synovial lining or intimal layer: Normally, this layer is only 1-3 cells thick.
normal synovial lining
Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, copyright 1991, 1995, 1997. Used by permission of the American College of Rheumatology.
In RA, this lining is greatly hypertrophied (8-10 cells thick). Primary cell populations in this layer are fibroblasts and macrophages.
Synovial lining in RA
Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, copyright 1991, 1995, 1997. Used by permission of the American College of Rheumatology.
2. Subintimal area of synovium: This is where the synovial blood vessels are located; this area normally has very few cells. In RA, however, the subintimal area is heavily infiltrated with inflammatory cells, including T and B lymphocytes, macrophages and mast cells. The intense cellular infiltrate is accompanied by new blood vessel growth (angiogenesis).
In RA, the hypertrophied synovium (also called pannus) invades and erodes contiguous bone and cartilage. As such, it can be thought of as a tumor-like tissue, although mitotic figures are rare and, of course, metastasis does not occur.
Cartilage
Composed primarily of type II collagen and proteoglycans, this is normally a very resilient tissue that absorbs considerable impact and stress. In RA, its integrity, resilience and water content are all impaired. This appears to be due to elaboration of proteolytic enzymes (collagenase, stromelysin) both by synovial lining cells and by chondrocytes themselves. Polymorphonuclear leukocytes in the synovial fluid may also contribute to this degradative process.
Bone
Composed primarily of type I collagen, invading synovium causes erosion of contiguous bone via release of prostaglandins and proteases by synovial cells and, possibly, by osteoclasts.
Synovial Cavity
Synovial Cavity Normally only a "potential" space with 1-2ml of highly viscous (due to hyaluronic acid) fluid with few cells. In RA, large collections of fluid ("effusions") occur which are, in effect, filtrates of plasma (and, therefore, exudative - i.e., high protein content). The
synovial fluid is highly inflammatory. However, unlike the rheumatoid synovial tissue that is infiltrated with lymphocytes and macrophages but not neutrophils, the predominant cell in the synovial fluid is the neutrophil.
(top of section)
(top of page)
The radiographic features of this disease correlate well with the histopathologic changes described above. Normal synovium lines, and is anchored to, both sides of the joint. The hypertrophied rheumatoid synovium begins its invasion of bone at these sites of attachment and this is seen radiographically as erosions on either or both sides of the joint. In addition to bone erosion, the height of cartilage is progressively and symmetrically reduced, consistent with a degradative process from within cartilage (chondrocyte mediated) or from exposure to synovial fluid (neutrophil mediated).
Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, copyright 1991, 1995, 1997. Used by permission of the American College of Rheumatology.
Synovial macrophages & Fibroblasts Inflammatory Mediators Other contributors to Inflammation Unanswered Questions
Synovial macrophages and fibroblasts interact to perpetuate inflammation
Most of our knowledge of the inflammatory process and cellular infiltrate in the rheumatoid joint comes from the study of synovium in established, rather than early, disease. CD4+ T cells, B cells and monocytes-macrophages migrate into, and remain in the synovial interstitium, presumably as a result of specific chemotactic stimuli and interaction of cellular adhesion molecules with counterligands expressed on extracellular matrix molecules (e.g., collagen, fibronectin). Neutrophils, in contrast, are found almost exclusively in the synovial cavity (fluid) and only rarely in the synovial tissue. Their migration through the synovial interstitium and across the synovial lining into the joint cavity may reflect lack of expression of specific adhesion molecules for extracellular matrix constituents.
According to the "T cell centric" theory of RA, activation of CD4+ cells would trigger and maintain the inflammatory process in the rheumatoid joint.
Interestingly, although large numbers of CD4+ cells persist in the synovium throughout the disease course, they appear to be inactive in the chronic phase of the disease. For example, expression of surface antigens (such as IL2 and transferrin receptors), and secretion of specific cytokines (e.g., IL2, IL4 and g-IFN), that are associated with an activated T cell state are very low.
Cellular Sources of Synovial Cytokines in RA
| Products of T cells | IL-2 IL-3 IL-4 IL-6 IFNg TNFb GM-CSF |
In contrast, cytokines known to be produced primarily by "effector" cells (macrophages) and connective tissue cells (fibroblasts) are expressed in abundance in RA synovium and synovial fluid, as measured by ELISA or mRNA studies. These cytokines include IL1, IL6, TNF, IL8 and GM-CSF. According to the alternative theory (the "macrophage-fibroblast theory") of RA, these two cell types appear to be largely responsible for creating a self-perpetuating state of chronic inflammation in which T cell participation may no longer be critical. In this scenario, the activated macrophage continuously secretes IL-1 and TNF which maintain the synovial fibroblast in an activated state.
Reprinted with permission from Weaver & Graziano: Anticytokine Therapy in the Treatment of Rheumatoid Arthritis. A Continuing Education Program for Physicians offered through the University of Wisconsin Medical School under an unrestricted Educational grant from Wyeth Ayerst.
The fibroblast, in turn, secretes large amounts of: a) cytokines - IL6, IL8 and GM-CSF; b) prostaglandins; and c) protease enzymes. GM-CSF feeds back to promote the maturation of newly recruited monocytes to macrophages. IL-8 and IL-6 contribute to the recruitment and/or activation of yet other cell populations, while the prostaglandins and proteases act directly to erode and destroy nearby connective tissues such as bone and cartilage. This process is elaborated further below.
Inflammatory mediators in RA
In addition to activating synovial cells to secrete inflammatory mediators, IL-1 and TNF also have profound systemic effects.
| Cellular | Systemic |
|
|
Some of these systemic effects are mediated via the induction of IL-6 synthesis.
Mature plasma cells that secrete rheumatoid factor are another prominent cellular component of rheumatoid synovium. The stimulus for maturation of B cells to immunoglobulin-secreting plasma cells has classically been ascribed to CD4+ T cells; however, as already noted, CD4+ T cells are not activated in the chronic phase of rheumatoid arthritis. IL-6, however, is a potent stimulus for maturation of B cells to plasma cells. Thus, synovial fibroblasts are likely providing the "T cell independent" stimulus for continuous plasma cell activation and rheumatoid factor production. IL-6 also suppresses albumin synthesis by the liver and stimulates acute phase protein synthesis. IL-6, therefore, contributes significantly to ESR elevation.
Effects of IL-6 |
|
| B cell maturation |
|
| Hepatocyte stimulus |
|
Neutrophils are recruited in very large numbers to the rheumatoid cavity where they can be aspirated in the synovial fluid. Complement activation is not a prominent feature of RA. Therefore, C5a is unlikely to contribute significantly to the recruitment of neutrophils to the joint. IL-8, however, is also a potent and specific chemotactic stimulus for neutrophils. Since synovial fibroblasts line the joint cavity, their elaboration of this cytokine into the joint cavity is likely to explain the selective recruitment of neutrophils to the synovial cavity. Neutrophils in the synovial fluid are in an activated state, releasing oxygen-derived free radicals that depolymerize hyaluronic acid and inactivate endogenous inhibitors of proteases, thus promoting damage to the joint.
Prostaglandins and proteases are also secreted from synovial fibroblasts as the pannus invades contiguous bone and cartilage. PGE2 resorbs bone and contributes to the radiographically demonstrable erosions at the site of synovial-bone attachment. The proteases (collagenase, stromelysin and gelatinase) act enzymatically to degrade the collagen and proteoglycan matrix of bone and cartilage. This destructive effect is further compounded by IL1 (and TNF) which suppresses synthesis of these matrix molecules. Thus, IL1 provides a "double insult" to connective tissue by both promoting its degradation (by inducing synthesis of proteases) and preventing its repair (by suppressing synthesis of collagen and proteoglycans).
Other Contributors to the Inflammatory Process
Soluble mediators of inflammation that may diffuse in from blood and/or be formed locally within the joint cavity include kinins and complement. Kinins cause release of prostaglandins from synovial fibroblasts, and are also potent algesic (pain-producing) agents. Complement may be available for interaction with immune complexes to generate additional chemotactic stimuli.
Chondrocytes, like synovial fibroblasts, are activated by IL1 and TNF to secrete proteolytic enzymes. They may, therefore, contribute to the dissolution of their own cartilage matrix, thus explaining the progressive narrowing of joint spaces seen radiographically in this disease. Finally, the neuropeptide substance P is a potent vasoactive, proinflammatory peptide that is likely to contribute to joint destruction and probably explains the remarkable symmetry of this disease.
Unanswered questions
Two pieces in the middle of the puzzle remain inadequately explained in this theory of self-sustained inflammation, however. The first is the macrophage. What is the stimulus for its initial and continued recruitment to the joint? And what causes its initial activation? Immune complex deposition (containing a bacterial or viral antigen or rheumatoid factor) in blood vessel walls may lead to local induction of endothelial and monocyte adhesion molecules which, in turn, allows for migration of monocytes into the synovium. Once in the synovium, initial activation of monocytes/macrophages may be induced by g-IFN secreted by activated CD4+ cells. Chronic maintenance in the activated state, however, is presumably independent of g-IFN, but may be promoted by immune complexes (again containing a bacterial or viral antigen or rheumatoid factor itself). Support for this concept comes from synovial biopsies of RA synovium in which IgG, IgM and C3 can be demonstrated by immuno-fluorescence. GM-CSF, elaborated by the synovial fibroblast, may also feedback to sustain the macrophages in a mature, activated state, as already noted.
Second, what factor(s) is responsible for the hypertrophy of the synovial lining? The predominant cells in the lining are macrophages and fibroblasts. Mature macrophages do not undergo mitosis, and few mitotic figures are observed in the fibroblast population either. A tantalizing, but as yet unproven theory, is that apoptosis of the fibroblast population is suppressed. This results in prolongation of the life of the fibroblast population, leading to increased numbers.
(top of section)
(top of page)
Rational Approaches to the Treatment of Rheumatoid Arthritis
Conventional agents Prevention Targeting the Initiation Stage Targeting the Propagation Stage Targeting Distal Events Future - Gene Therapy?
Conventional agents have unknown mechanisms of action
Use of these agents was prompted largely by empiric observations of their apparent efficacy, not by "rational drug design". These include methotrexate, gold, D-penicillamine, hydroxychloroquine, and other cytotoxic agents including azathioprine and cyclophosphamide (more info on pharmacologic strategies in RA treatments). Methotrexate is the most effective of this group of drugs and was the mainstay of treatment of RA until recent FDA approval of several new drugs (more info on new treatments)(also, see ACR Highlights).
Prevention
Obviously, prevention is the most effective method of treatment but is not feasible until the cause of the disease is identified. If viral, vaccination would be a logical approach.
Targeting the initiation stage of disease
Several therapeutic strategies are currently under investigation:
- Disrupt antigen presentation by DR4 This approach utilizes antibodies directed against the peptide-binding region and/or the shared motif of DR4 found in 90% of RA patients. The antibody would presumably block presentation of antigen to the host T cell by way of steric hindrance. Alternatively, a peptide homologous to the shared epitope may disrupt the trimolecular complex (DR4-peptide-T cell receptor) by competing with native DR4 molecules for interaction with CD4+ T cells.
- Block T cell activation Block T cell activation Restricted T-cell receptor gene use in the activated T-cell population in RA has been observed. Peptide vaccines, based on the variable region gene elements of the b chain of the human T cell receptor of T cells found to be infiltrating human synovial tissue in RA, are currently being tested and look promising. Other therapeutic approaches in which activated T cells are depleted have been less successful. For example, treatment of patients with a monoclonal antibody directed against CD4 successfully reduced the number of circulating CD4+ T cells, but did not induce a significant clinical response in patients with rheumatoid arthritis.
Targeting the propagation stage of disease
Some approaches that are being studied or considered:
- Inhibit endothelial cell adhesion molecule expression This approach involves the administration of anti-ICAM, -ELAM, -VCAM, -VLA antibodies. The goal is to limit infiltration of synovium and synovial cavity by inflammatory cells. Clinical trials have been limited due to lack of humanized antibodies. Another approach is to inhibit angiogenesis in order to limit synovial hyperplasia.
- Inhibition of cellular proliferation For example, with anti-PDGF or -FGF antibodies, or by the use of agents that promote apoptosis (e.g., paclitaxel). The former presumes that there is enhanced cellular proliferation in rheumatoid synovium, but this remains doubtful.
- Inhibition of TNF-a and/or IL-1 Inhibition of TNF-a and IL-1 would be expected to reduce production of proteases, prostanoids, and other cytokines (IL-6, IL-8 and GM-CSF) in the rheumatoid joint and thereby reduce inflammation. There are several mechanisms by which TNF and IL-1 can be inhibited. These include administration of:
- monoclonal antibodies directed against TNF or IL-1
- antagonists of the TNF or IL-1 receptors
- soluble TNF or IL-1 receptors
- antiinflammatory cytokines (e.g., IL-4 and IL-10).
- monoclonal antibodies directed against TNF or IL-1
The first three approaches will theoretically block the interaction of a cytokine with its cognate membrane bound receptor, thereby preventing cell activation and release of inflammatory molecules The last approach seeks to counterbalance the proinflammatory effects of IL-1 and TNF.
The most successful clinical responses to date, using cytokines or cytokine inhibitors in RA, have been with TNF inhibitors, namely a soluble TNF receptor and a humanized monoclonal antibody directed against TNF. These are discussed in detail elsewhere. (see Rheumatoid Arthritis and ACR Highlights) An initial trial with a soluble IL-1 receptor did not show efficacy but is likely to have targeted the wrong IL-1 receptor; studies are in progress currently with a recombinant form of the endogenous IL-1 receptor antagonist.
It should be noted that corticosteroids inhibit production of many cytokines (e.g., IL-1, TNF, IL-6 and IL-8), of prostanoids, and of proteolytic enzymes. However, these beneficial effects of steroids are counterbalanced by a number of undesirable side effects that limit the usefulness of corticosteroids in this disease such as weight gain, hypertension, osteoporosis, and ischemic necrosis of bone.
Targeting distal events
Nonsteroidal anti-inflammatory agents exert their anti-inflammatory effects by inhibiting synthesis of prostanoids via cyclooxygenase (COX) inhibition. New classes of NSAIDs are being developed that specifically inhibit COX-2 (rather than both COX-1 and -2), and these are likely to be considerably safer than conventional agents. (more info on Cox-2) Inhibitors of metalloprotease enzymes, and kinin and substance P receptor antagonists, are also in development and/or clinical trial.
Future - gene therapy?
Therapeutic proteins can be introduced and "overexpressed" in rabbit synovia via viral or nonviral gene transfer vectors. Transduction of synovial cells and chondrocytes with the IL-1 receptor antagonist gene has been successfully accomplished in vitro and in vivo in animal studies, but beneficial results are short-lived. The feasibility of this approach in humans is currently being evaluated. Optimal vectors for gene transfer in humans remain to be identified.
(top of section)
(top of page)
1. Arend, W. P. The pathophysiology and treatment of rheumatoid arthritis. Arthritis and Rheumatism 40: 595-597, 1997
2. Moreland LW, Heck Jr LW, Koopman WJ. Biologic agents for treating rheumatoid arthritis. Arthritis and Rheumatism 40:397-409, 1997
3. Fox, D. A. The role of T cells in the immunopathogenesis of rheumatoid arthritis. Arthritis and Rheumatism 40:598-609, 1997
4. Arend, W. P. and Dayer, J.-M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor-a in rheumatoid arthritis. Arthritis and Rheumatism 2:151, 1995
5. Struyk, L., Hawes, G. E., Chatila, M. K., et al. T cell receptors in rheumatoid arthritis. Arthritis and Rheumatism 5:577, 1995
