Alternative Therapy For Rheumatoid Arthritis
Andrew Halpner, Ph.D., with contributions from Dr. Bagchi (InterHealth Nutraceuticals)

    Arthritis is one of the most prevalent chronic health problems in the United States, affecting nearly 43 million people. Although arthritis is often thought of as a disease that predominantly affects the elderly, it is the number one disability affecting those over the age of 15. In fact, more than half of those affected by arthritis are under the age of 65, and almost 300,000 of those affected are children. Each year arthritis is responsible for 44 million outpatient visits, almost one million hospitalizations, and is second only to heart disease in terms of its effect on disability from work. As might be imagined from these statistics, the toll that arthritis takes on the health care industry is substantial, costing the United States approximately $65 billion each year in health-related expenses. Unfortunately, the prevalence of arthritis does not appear to be improving, and by the year 2020 the Centers for Disease Control predicts that almost 60 million Americans will suffer from some form of this disease.

    While the term arthritis may bring to mind a simple condition characterized by painful joints and difficulty performing certain tasks, arthritis actually encompasses more than 100 different diseases. Of these different forms of arthritis, however, osteoarthritis (OA) and rheumatoid arthritis (RA) are among the most common.

    Rheumatoid Arthritis: Rheumatoid arthritis is not a “new” disease. One of the first descriptions of a disease resembling RA can be found in the Caraka Samhita, a medical text from India, and dates back as far as 500 B.C. Another ancient reference to the disease dates to 100 B.C. in Rome when Scribonius Largus described a polyarthritic condition occurring mainly in elderly women that closely resembled what we now understand to be RA. Rheumatoid arthritis currently affects approximately two million Americans, and about one percent of the population worldwide. However, the pathology and progression of RA is somewhat different from that of OA. Unlike OA, RA often develops suddenly, within weeks or months and generally begins between the ages of 25 and 50. Non-weight-bearing joints such as the shoulders and elbows are usually affected bilaterally, and a significant amount of redness, tenderness, swelling and inflammation is often present. This form of arthritis often results in a feeling of sickness, fatigue, and may be accompanied by weight loss as well as fever. Morning joint stiffness lasting for an hour or longer is relatively common. Subcutaneous nodules that form over bones may also be present. While the reasons are not completely understood, three times as many women compared with men are afflicted with rheumatoid arthritis. Some patients will experience a monocyclic course of the disease that may abate within two years, while others will experience a polycylic, or progressive course. Of all the forms of arthritis, RA tends be one of the most serious and disabling forms of the disease, with 16 percent of those who have had the disease for 12 or more years becoming completely disabled. Lifespan has also be shown to be shortened by approximately seven years in men and three years in women, which is equivalent to the increased mortality observed in those with diabetes and Hodgkin disease.


Etiology
    While RA is classified as an autoimmune disease, the exact causes that result in its development remain a mystery. What is known is that many different and complex factors are involved. Some cases of OA may be the result of years of “wear and tare” on joint structures, while other forms of OA can be traced to an injury, infection, or metabolic disorder. However, RA does not result from overuse of a joint or from injury, but rather from an autoimmune problem in which the body attacks and damages its own tissue. The damage that occurs in RA appears to be propagated by cytokines (important regulatory chemicals within the body) secreted by T-cells of the immune system in response to certain autoantigenic stimuli within the joint. In other words, the body’s immune system is, for some unexplained reason, identifying some component or components of the joint as containing antigens against which a response from the immune system should be carried out. Various immunological factors are involved, including, but not limited to, CD4/inducer lymphocytes, CD4 memory cells, macrophages, neutrophils, and tumor necrosis factor (TNF). One of the most likely candidates for this autoantigenic stimulus is the collagen component of cartilage, specifically type II collagen. Some researchers believe that an infection may trigger the initial inflammation in a joint, which in turn triggers the autoimmune response by the body. However, genetics and other factors, including stress, may also play a role.

    To fully understand the deterioration that is occurring in arthritic conditions, it is important to have a basic knowledge of the structure and components of a joint. When bones meet at a joint, such as the hip or elbow, the ends of the bones are covered with cartilage. This cartilage allows for flexibility and motion as well as provides a cushion against the impact of various forces on the bone. The detailed structure of cartilage is complex, but can be simplified into two major components, collagen and proteoglycans. Proteoglycans are large protein molecules attached to large carbohydrate chains called glycosaminoglycans. These proteoglycans help to provide a matrix in which the collagen as well as water can reside. There are a number of different types of collagen, but type II collagen accounts for the majority of what is found is cartilage. Type II collagen is composed of three identical chains (termed α-1 chains), which form a triple helix. This interconnected network of collagen and proteoglycans is crucial in order to maintain joint flexibility and resistance to stress and fracture. In RA, autoantigenic responses, most likely triggered by type II collagen, ultimately result in the progressive inflammation, pain, and deterioration characteristic of this disease.

   Regardless of the initial cause, a progressive degeneration of the structure and function of the joint takes place, making normal activities of life increasingly difficult. In the case of RA, the body is unable to recognize its collagen as normal tissue and in turn attacks it as if it was a foreign invader. A novel approach to the treatment of RA termed “oral tolerance,” has been the focus of significant positive scientific research. Oral tolerance is a treatment in which small amounts of type II collagen (the material that the body is destroying) are presented to the gastrointestinal tract. What results is a down regulation of the body’s ability to destroy its own collagen and a resulting improvement in the symptoms and progression of the disease. However, before we explore this treatment further, it is important to understand traditional treatment options.


Current Treatment Options
    Traditionally, treatment options for those with rheumatoid arthritis are non-steroidal anti-inflammatory drugs (NSAIDs) alone or in combination with what are known as disease-modifying antirheumatic drugs (DMARDs). As is well known, chronic use of NSAIDs, especially in the elderly is linked to numerous side effects including gastrointestinal bleeding, and renal malfunctions. Even the newer generation of COX-2 inhibitors such as Vioxx and Celebrex are not without their own problems. While these drugs do reduce inflammation, they do not address the underlying cause of the arthritis and therefore cannot alter the progression of the disease. Also, prolonged used of these newer COX-II inhibitors in the elderly can result in side effects similar  to those seen with traditional NSAIDs. Disease-modifying antirheumatic drugs attempt to more fully address the underlying pathology of RA by slowing the progression of the pathology. One of the components of this disease in addition to inflammation is microvascular injury, coupled with the formation of new capillaries. Many of the DMARDs attempt to inhibit the formation of new capillaries as well as address the underlying inflammation, although many of the mechanisms by which they may work are not completely understood. This category of drugs includes azathioprine, corticosteroids, gold, hydroxychloroquine, methotrexate, sulfasalazine, and a number of newer medications such as leflunomide, etanercept, and infliximab. While these medications have been shown to offer clinical improvement to those with rheumatoid arthritis, they also can be associated with significant toxicity and side effects including myelosuppresion, lymphoproliferative disorders, macular damage, thrompocytopenia, osteoporosis, hyperglycemia and hepatotoxicity. Another factor with respect to the newer medications that should be noted is cost. The monthly expense for etanercept and infliximab (both of which must be injected) can exceed $1,000.

Involvement of the Immune System and Oral Tolerance
    When the immune system is functioning properly, it is able to recognize and identify foreign substances in order to help eliminate them from the body. One type of immune cell that is particularly important in this process is the T cell, a type of specialized white blood cell. T cells can be classified in a number of different categories depending on their function. “Helper” T cells have the function of releasing factors that help increase or decrease the immune response. These “helper” T cells have been further classified into Th-1 and Th-2 subsets. Th-1 cells amplify proinflammatory responses, while Th-2 cells limit such responses. “Killer” T cells have the function of attacking and destroying antigens. Another type of cell called the B cell is also crucial for the functioning of the immune system, as the B cell is responsible for the production of antibodies. In a normal individual, the immune system does not seek out and destroy healthy tissue. This is in part due to the fact that T cells that have specificity for antigens on normal, healthy tissue are either suppressed or destroyed prior to being released into circulation. Unfortunately, in the case of rheumatoid arthritis, T cells with self-antigens for type II collagen are not properly destroyed or suppressed, resulting in the destruction that is a characteristic trademark of this disease.

Oral Tolerance
    If one could decrease the activity of T cells that are releasing joint-destroying factors, one could improve the outcome for patients with RA. One such method to achieve this is termed ”oral tolerance,” and is a concept that may prove useful in the treatment of autoimmune diseases. Oral tolerance (OT) describes a state of immune hyporesponsiveness following the oral ingestion of a protein. In other words, OT is a method by which one is able to induce a peripheral immune tolerance (down regulation) to a particular antigen by presenting specific amounts of that antigen to the gastrointestinal system. While this concept may at first sound “alternative” or “unproven,” the concept of oral tolerance has existed since 1911, and the traditional medical literature is filled with papers describing this mechanism and how it might benefit those with autoimmune diseases.

Clonal Anergy
    Another mechanism by which an orally administered protein can induce a down regulation of an immune response is via a mechanism called clonal anergy. This situation results from the ingestion of high doses of an antigen, which in turn induces a state of unresponsiveness from overactive helper T cells (Th1 cells). The T helper cells are not deleted, but they are rendered incapable of responding to a specific antigen. In essence they are “turned off” or anergized, and will no longer recognize the antigen as a target for destruction.


Clinical Studies
    It is via the mechanism of oral tolerance that type II collagen has been studied for its ability to benefit those with RA. As previously stated, for those with RA, healthy type II collagen acts as an antigen against which the body’s immune system is reacting. This makes sense, as type II collagen is the most abundant structural protein present in cartilage.

    Numerous animal models of arthritis have demonstrated significant benefit from orally administered, native (undenatured) type II collagen. Oral collagen administration has been able to suppress almost all experimentally inducible forms of RA in animals, including antigen-induced arthritis, adjuvant arthritis, streptococcal cell-wall arthritis, and siliconeinduced arthritis. These impressive results led to the investigation of native type II collagen supplementation in humans with RA. In 1993, the results of both an open-label, pilot trial as well as a phase II trial in humans were published in the prestigious journal SCIENCE. In a pilot trial, ten patients diagnosed with RA were taken off of their immuno-suppressive and disease-modifying drugs and were given 0.1 mg of native type II collagen for one month, followed by 0.5 mg of native type II collagen for the next two months. Six of the ten subjects experienced a significant improvement (defined as > 50 percent compared with baseline) in swollen and tender joint counts, as well as morning stiffness, 15 minute walk time, grip strength time, and erythrocyte sedimentation rate (a measure of inflammation). One subject who was previously being treated with methotrexate experienced complete remission, which continued for 26 months. No adverse effects were noted. Given those exciting results, a placebo-controlled, phase II follow up trial was performed. This trial consisted of 60 subjects with severe, active RA. Participants were randomized to either native type II collagen or placebo for 90 days. At one, two, and three months, there was a significant improvement (P < 0.05) in the number of swollen joints, the number of painful and tender joints, and 15 minute walking time (at two month’s time P = 0.06 for tender or painful joints). Four patients in the collagen group, compared with zero patients in the placebo group experienced complete remission of the disease. Again, one of the most notable findings was the lack of side effects as a result of the treatment. This is important given the side effects that can be present with various DMARDs and NSAIDs.

    In a fifth double-blind, placebo controlled study out of Germany, 90 subjects with early RA were divided into those receiving 1 mg of collagen, 10 mg of collagen, or placebo. At the end of study three patients in the 10 mg, one patient in the 1 mg and no patients in the placebo group experienced marked improvement. While these results may not appear very impressive, the authors were surprised by the degree of benefit given the small subset of patients. In another German study, 1 mg and 10 mg of undenatured type II collagen resulted in reduced type II collagen antibody titres in patients showing a clinical response. This study also suggested that 10 mg was a more effective dosage than 1 mg. These studies provide the basis and rationale for the use of native type II collagen as a safe and effective modality of treatment for those suffering with rheumatoid arthritis.


The Importance of a Native (Undenatured) Form of Collagen
    One important variable in the ability of type II collagen to confer oral tolerance is the presence of native type II collagen. In other words, the collagen must be type II collagen, and must be present in its undenatured, three dimensional, triple helical structure. Unfortunately, many products on the market do not contain any type II collagen at all, and most products that do contain type II collagen have undergone harsh manufacturing procedures. This renders the collagen denatured and no longer able to illicit an immune response once ingested. In fact, no peer-reviewed studies exist to support the use of denatured collagen in RA, and one study has shown denatured collagen to have no impact of the severity of the disease. In order to insure that undenatured type II collagen is present, highly sensitive ELISA assays must be performed to confirm that the material will be biologically active.

Dose
    Dr. David E. Trentham, leading researcher in the field of RA at Harvard University, supports the use of native type II collagen and recommends a dose of 10 mg to be taken with water at bedtime on an empty stomach.


References
Aceves-Avila, F. J. The antiquity of rheumatoid arthritis: A reappraisal. J Rheumatol 28:751-757;2001.

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