Reprinted with permission of Life Extension®.
The word arthritis literally means inflammation of the joint. Joints can become inflamed for many reasons, but most of us think of arthritis usually as one of two kinds: osteoarthritis or rheumatoid arthritis. These are two very distinct entities, and they are both a huge source of discomfort and disability. A significant amount of new research provides an understanding of both kinds of arthritis so that those who are afflicted may find relief.
The prevalence of arthritis and other rheumatic conditions in the United States is very high and is projected to rise as the population ages. Arthritis is a leading cause of disability among persons over age 64. In this protocol, you will learn about the underlying cause of most forms of arthritis and how you may be able to reverse these degenerative processes.The Normal Joint
To understand diseases of the joint, we need to look at the normal healthy joint. Joints are held together by a joint capsule that is designed to allow smooth movement between adjacent bones. In the type of joint that is commonly affected by arthritic diseases (the highly movable joints), the bone ends are covered by articular cartilage over which the joint moves. A synovial membrane encloses the joint space itself. This thin membrane secretes synovial fluid that lubricates the space between the cartilage-covered, joint-forming bones. The cartilage contains no blood vessels or nerves and receives its nutrients by diffusion from the synovial fluid and from the bone.
Joint function depends on the health of the cartilage in the joint and the synovial membrane. Cartilage is a gel-like substance that acts as a shock absorber, essential for smooth and easy movement in the joint. Cartilage gets its elasticity from collagen fibers and its sponge-like quality from water, held together by a structure of big molecules called proteoglycans. Special cells (called chondrocytes) in the cartilage produce collagen and proteoglycans (Fassbender 1987). Joints can withstand enormous pressure by slowly releasing water from the cartilage.
As we age, the ability to restore and maintain a normal cartilage structure decreases. The activity of important repair enzymes is reduced, the water content diminished, and the joints become more prone to damage. Scientists are just now beginning to understand the specific mechanisms involved in the development of arthritis and how to effectively correct them.
Conventional medicine previously offered only symptomatic, temporary relief from chronic arthritic conditions. High doses of the nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in reducing symptoms quickly but can cause side effects such as ulcers and gastrointestinal bleeding, and NSAIDs do not stop the progression of arthritis. In the long run, some antiarthritic drugs may actually worsen the condition by accelerating joint destruction.
However, in the last few years, research has brought hope to this dismal picture. New prescription drugs neutralize some of the inflammatory factors involved in joint cartilage destruction. Also, a compelling body of evidence shows that the proper combination of natural therapies such as fish and borage oils may work better than some of these prescription drugs. By taking advantage of this nutritional information, one can achieve not only symptomatic relief, but actually intervene at the root of the problem and help the body to rebuild functioning joints.Biochemical Mechanisms of Arthritis
Inflammation is a living tissue response to mechanical, chemical, and immunological challenge. Normal aging often results in the excessive production of autoimmune factors that destroy joint cartilage and other tissues in the body. Suppressing these inflammatory factors is a critical component of an effective arthritis treatment program.
Inflammation is partially characterized by high levels of arachidonic acid products which are metabolized along two different enzymatic pathways: cyclooxygenase (COX) and lipoxygenase, leading to prostaglandin (PGE-2) and leukotriene (LTB4). Some physicians believe these are the most important mediators of inflammation (Srivastava et al. 1992). PGE2 and LTB4 play a crucial role in arthritis by causing resorption of bone, stimulating the secretion of collagen breakdown enzymes, and inhibiting the formation of proteoglycans--the building blocks of cartilage.
The destruction of cartilage and bone in both osteoarthritis (OA) and rheumatoid arthritis (RA) is related to the action of matrix enzymes (metalloproteinases), which include collagenases and stromelysins (Birkedal-Hansen et al. 1993; Hill et al. 1994). Some of these enzymes have proinflammatory characteristics and some have anti-inflammatory properties. The varying balance between these forces probably accounts for the variation in disease activity as it flares up and subsides. These enzymes are under the control of cytokines, such as interleuken 1 (IL-1b) and tumor necrosis factor-alpha (TNF-alpha), which are highly activated in RA and are elevated in the synovial membrane, the synovial fluid, and the cartilage of OA patients (Saklatvala 1986). Cytokines are proteins that carry messages between cells and regulate immunity and inflammation. In animal models, inhibition of TNF-alpha results in decreased inflammation, while inhibition of IL-1b effectively prevents cartilage destruction (Plows et al. 1995; Frye et al. 1996).
Health-conscious people should become familiar with proinflammatory cytokines because excess levels cause or contribute to many disease states. The following acronyms represent the most dangerous proinflammatory cytokines:
- Tumor necrosis factor alpha (TNF- a)
- Interleukin-6 (IL-6)
- Interleukin-beta (IL-1b)
Data from many studies confirm the important role of TNF-alpha in regulating production of both inflammatory and anti-inflammatory mediators in RA. Because of the demonstrated excess of proinflammatory cytokines, such as TNF-alpha, it was hypothesized that a blockade of TNF-alpha should be beneficial. Several experimental as well as clinical studies have been conducted with an anti-TNF-alpha antibody (Paulus et al. 1990). The results have confirmed that suppression of TNF-alpha is an effective treatment modality in treating RA. In addition to inhibiting TNF-alpha, it is also crucial to suppress excessive levels of PGE2, LTB4, IL-1, and IL-6. We now know how to suppress all of these proinflammatory factors that are involved in joint cartilage destruction.Current Medical Treatment
- Partially Effective, But Cost-Prohibitive Drug
- Following Protocol
The conventional treatment for both OA and RA has consisted of NSAIDs, including aspirin. Even stronger disease-modifying drugs such as corticosteroids, gold salts, and methotrexate are often prescribed for RA in an aggressive attempt to stop the development of the disease. These drugs are all aimed at alleviating pain and reducing inflammation. They can sometimes be effective, but more often, however, they prove unsatisfactory and many times intolerable due to toxicity. High-dose aspirin, for example, is effective, but it often causes gastric irritation and tinnitus (ringing in the ears) with the large dosages needed (Hubsher et al. 1979). Other NSAIDs may have an even greater risk for serious side effects, which limit their use. These treatments are only symptomatic because they do not act on the causes of arthritis and do not stop the progression of the disease. In fact, the opposite has shown to be true. It has been demonstrated in some studies that NSAIDs actually have an inhibitory effect on cartilage repair and accelerate cartilage destruction (Solomon 1973; Ronningen et al. 1979; Brooks et al. 1982; Newman et al.1985; Shield 1993).
How can it be that NSAIDs help relieve symptoms but facilitate cartilage destruction at the same time? NSAIDs exert their analgesic and anti-inflammatory effects through the inhibition of the enzyme COX. The discovery that two forms of COX (COX-1 and COX-2) exist has clarified the dual nature of NSAIDs (Needleman et al. 1979). While relieving pain and inflammation through COX-2 blockade, they also block, via COX-1, the biotransformation of arachidonic acid to substances that carry out various homeostatic (balancing) physiological functions, one of which is to protect the gastrointestinal mucosa and limit gastric acid output.
While NSAIDs inhibit PGE2 synthesis through a COX-2 blockade, they fail to influence the TNF-alpha and IL-1b activation of cartilage-destroying enzymes. NSAIDs also create what is known as a leaky gut that allows unwanted, partially digested protein products to enter the bloodstream via the intestine (Hollander 1999). These products can cause more inflammation and further activate an already overstimulated immune response.
With this enhanced understanding of the underlying mechanisms for current medical treatment, researchers are now looking for new compounds that will relieve pain and inflammation and enhance the repair process in the joints without inhibiting important physiological functions. COX-2-specific inhibitors (e.g., Vioxx and Celebrex), are widely promoted, but they are showing similar side effects because they do not leave the COX-1 pathways totally unaffected. Another problem with COX-2 inhibitors is that while they block the formation of PGE2 from arachidonic acid, they do not adequately suppress the formation of LTB4 from arachidonic acid. In order to suppress both PGE2 and LTB4, it is necessary to inhibit their common precursor, which is arachidonic acid.
As can be seen from the chart, arachidonic acid converts to PGE2 by using the COX-2 enzyme. Arachidonic acid also converts to the proinflammatory cytokine LTB4 using the enzyme 5-lipooxygenase. Since drugs such as Celebrex only inhibit COX-2, they potentially leave more arachidonic acid available to convert to joint-destroying LTB4 (via the lipooxygenase pathway).
Due to heavy marketing practices, Celebrex and Vioxx quickly became highly popular drugs. However, the FDA has written to both companies accusing them of minimizing side effects and overpromoting positive effects.
Celebrex could lead to bleeding in persons taking warfarin; serious gastrointestinal (GI) symptoms can occur without warning. Celebrex should not be used by persons allergic to sulfa, nor by people who have an asthma attack upon taking aspirin. In addition, Celebrex and Vioxx are not for acute pain. We intentionally do not discuss these drugs in detail because of their toxicity potential.A Partially Effective, But Cost-Prohibitive Drug
Enbrel is an FDA-approved drug that treats RA by suppressing the destructive cytokine, TNF-alpha. Enbrel is relatively safe, with the primary side effect being injection site reactions. Since TNF-alpha isneeded to fight acute infectious disease, when one has a serious infection, Enbrel therapy is temporarily discontinued until the infection subsides.
The high cost of Enbrel makes it prohibitive for most people (about $11,000 a year). It usually requires two visits every week to a physician's office for injections though some patients can administer their own injections at home. Many HMOs insist that arthritis patients use less costly COX-2 inhibiting drugs such as Celebrex or Vioxx in lieu of the more expensive Enbrel. COX-2 inhibiting drugs, however, are not as effective as Enbrel.
While Enbrel is only approved by the FDA for RA, it may also be effective in protecting against the cartilage destruction that occurs in OA. Both TNF-alpha and IL-1b have been shown to play a role in the cartilage destruction and inflammatory process characteristic of OA (Feldman et al. 2000). Even if one has insurance that will pay for Enbrel, a diagnosis of RA is still required for an insurance company to cover the cost of Enbrel. This means that those with OA face the prospect of both having to pay the $11,000 yearly out-of-pocket cost and locating a physician willing to prescribe Enbrel for an unapproved use, that is, the treatment of OA.
Enbrel has demonstrated impressive clinical results, but it only suppresses TNF-alpha. To adequately deal with the multiple processes involved in arthritic cartilage destruction, it is usually necessary to also reduce elevated levels of PGE2, LTB4, IL-1, IL-6, and TNF-alpha.
The Life Extension Foundation has identified safe methods to inhibit these multiple inflammatory factors involved in the arthritic process.Following the Protocol
OA and RA have certain features in common, mainly inflammation. Because the inflammatory pathways are similar whatever the cause, some of the treatments will be similar for both forms of arthritis, whereas in some cases research has been more firmly dedicated to one kind or the other. In the protocol that follows, we have tried to be clear about dietary changes, drugs, hormones, and supplements that are being overlooked by conventional physicians.Chronic Inflammation...The Underlying Villain
Chronic inflammation inflicts devastating effects, especially as we grow older. The pathological consequences of inflammation are fully documented in the medical literature (Licinio et al. 1999; Deon et al. 2001; Kanda 2001; Smith et al. 2001). Regrettably, the dangers of systemic inflammation continue to be ignored, even though proven ways exist to reverse this problem.
Aging results in an increase of inflammatory cytokines (destructive cell-signaling chemicals) that contribute to many degenerative diseases. RA is a classic autoimmune disorder in which excess levels of cytokines such as TNF-alpha, IL-6, and IL-1b are known to cause or contribute to the inflammatory syndrome (Feldmann et al. 1996). Some of these same inflammatory factors can contribute to OA (Fernandes et al. 2002; Futani et al. 2002; Nishimura et al. 2002).
While chronic inflammation often symptomatically manifests as arthritis, it is also involved in diseases as diverse as atherosclerosis, heart valve dysfunction, congestive heart failure, Alzheimer's disease, and even cancer. In elderly people with multiple degenerative diseases, blood levels of C-reactive protein are often sharply elevated, indicating the presence of an underlying inflammatory disorder. When a cytokine blood profile is conducted in those with high C-reactive protein, we usually find excessive levels of one or more of the inflammatory factors (TNF-alpha, IL-6, IL-1b, and LTB4).
Scientists have identified dietary supplements and prescription drugs that can reduce levels of the proinflammatory cytokines. The docosahexaenoic acid (DHA) fraction of fish oil, for example, is the best documented supplement to suppress TNF-alpha, IL-6, IL-1b, and LTB4 (Khalfoun et al. 1997; Watanabe et al. 2000; Deon et al. 2001). Research studies in healthy humans and in persons with rheumatoid disease show that fish oil suppresses these dangerous inflammatory factors by up to 90% (James et al. 2000).
Other cytokine-lowering supplements are dehydroepiandrosterone (DHEA) (Daynes et al. 1993; Kipper-Galperin et al. 1999; Haden et al. 2000), vitamin K (Reddi et al. 1995; Weber 1997), gamma-linolenic acid (GLA) (Purasiri et al. 1994; Mancuso et al. 1997; Dirks et al. 1998; DeLuca et al. 1999), and nettle leaf extract (Teucher et al. 1996). Antioxidants (such as vitamin E and N-acetyl-cysteine) may also lower proinflammatory cytokines (Gosset et al. 1999; Devaraj et al. 2000) and protect against their toxic effects (Winrow et al. 1993; Horton et al. 2001; Langlois et al. 2001).
Prescription drugs such as Enbrel directly bind to TNF-alpha and block its interaction with TNF cell surface receptors. Enbrel has demonstrated significant clinical improvement in RA patients, as have high-dose fish oil supplements (Kremer 2000). There are no side-by-side comparison studies to determine whether fish oil or Enbrel is better.Continued
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