Rheumatoid Arthritis- General Overview- Part IV

(7/6/10)- Glucosamine and chondroitin are herbal supplements that are popular with arthritis sufferers even though there are many medical professionals who doubt their efficacy. There have been several studies that raised doubt as to their effectiveness. A study that was published in the New England Journal of Medicine in 2006 showed that they were no better than placebos.

With that said, there are many who still swear by these two supplements. They come in tablet form but there is also a popular drink that contains the supplements that is growing greatly in popularity among the public.

The beverage is called Elations, and is especially being used by people who can not swallow pills.

According to a 2009 report from Mintel, a market research firm, 25% of arthritis sufferers use glucosamine, chondroitin or other supplements for pain relief from arthritis.

Revenues for Elation have grown to$40 million in revenue in 2009 from $12 million in 2008, and are projected to rise to $75 million this year. Sunny Delight Beverage Company, the firm that manufactures Elations spent $10.4 million on advertising in 2009, according to Kantar Media, a unit of WPP that tracks ad spending.

(12/08)- According to the Agency for Healthcare Research and Quality, in 2005, 21 million adults – approximately 9.5% of the adult population – either visited or called a doctor for a prescription to relieve them of pain caused by arthritis.

The data also revealed that the incidence of arthritis varies widely between different ethnic groups, with 10.5% non-Hispanic white adults reporting having arthritis, compared with just 5.9% of Hispanic adults and 4.3% of non-Hispanic Asians.

The condition also appears to afflict more women than men (11.9% versus 7.1%). Source: Arthritis: Use and Expenditures among U.S. Noninstitutionalized Population, 2005. Agency for Healthcare Research and Quality. November 5th 2008.

(11/7/06)- Although glucosamine and chondroitin, either taken separately or together are the most commonly used natural supplements in battling the pain of arthritis, there is some evidence that phellodendron and a citrus-peel extract in combination work equally as well in fighting the pain from osteosrthritis. The National Institutes of Health estimates that there are about 21 million American adults who suffer from this disease.

In osteoarthritis, cartilage begins to fray and wear away, causing joint pain and stiffness in the hands, knees, neck, hips and lower back. The bark of the phellodendron trees has been used for many years in Chinese medicines to help alleviate pain. There are about a dozen different brand names used for the product, but the most common one in this country is "Nexrutine," made by Next Pharmaceuticals Inc., a Carlsbad, Calif., company that is a major supplier of the extract.

The cost for phellodendron ranges from $20 to $30 for a month's supply. The Next product involves grinding up the bark of the tree from which berberine hydrocholoride is extracted. To boost the effect of the product, the company adds the citrus-peel extract that was found by the U.S. Department of Agriculture to have an anti-inflammatory action on cells in test tubes. The extract has never been tested on humans.

So far the combination of phellodendron and the citrus-peel extract are not market in this country, but Solanova LLC of Novato, California plans to begin marketing the product shortly.

(6/27/06)- David P. Hamilton wrote and excellent article entitled: "New Treatments for Rheumatoid Arthritis" in a recent edition of the Wall Street Journal that we will summarize below:

"Since December, regulators have approved two new biotechnology drugs for the crippling autoimmune disease, each of which attacks rheumatoid arthritis in an entirely new way. The new biotechnology drugs, Orencia and Rituxan, are often very effective, and can slow or even haltthe joint and bone deterioration characteristic of rheumatoid arthritis."

The article goes on to point out the fact that these new drugs can be very expensive to administer. Rituxan, which is sold by Genentech Inc. and Biogen Inc. costs $18,630 for a typical course of two infusions.

Orencia is made by Bristol-Myers Squibb costs about $17,500 a year for a patient without insurance. "Most insurance plans cover these and other RA drugs for patients who have failed earlier treatments, although some require co-payments of as much as 20% of the cost."

These treatments have been linked to some serious adverse reactions, which include fatal infusion reactions and increased risk of cancer. Orencia and Retuxin are known as TNF inhibitors that block a mechanism of infection. For more on TNF inhibitors please see our article Rheumatoid Arthritis Part II-TNF and Enbrel. Johnson & Johnson's Remicade and Abbott Labs Humira are two other TNF inhibitor treatment drugs.

These treatments are used in combination with older drugs. It may take several weeks before the right combination is set for this type of treatment. RA effects an estimated 2.1 million Americans according to the Arthritis Foundation. This is a distinct number not including those who suffer from osteoarthritis, "a breaking down of the cartilage in the joints, generally as a result of age."

Orencia acts by "preventing the activation of immune-system defenders known as T cells, which help lead the attack on joint tissues." Orencia is administered in a doctor's office or clinic for a 30-minute infusion every four weeks

Rituxan was already used to treat blood cancer called non-Hodgkin's lymphoma. This drug works by killing off immune-system watchdogs known as B cells. Rituxan requires two infusions, each lasting three to six hours, spaced two weeks apart.

"Most patients newly diagnosed with rheumatoid arthritis still begin treatment with older oral drugs such as methotrexate, a cancer drug that inhibits cellular metabolism." If this treatment does not work the majority of patients than move on to the TNF inhibitors, usually in combination with methotrexate.

(12/25/01)- reduced motion. (See below for a list of features of rheumatoid arthritis.)

Physical, chemical, and biologic agents, including mechanical trauma, exposure to excessive amounts of sunlight, x-rays and radioactive materials, corrosive chemicals, extremes of heat and cold, and infectious agents such as bacteria, viruses, and other pathogenic microorganisms can provoke the inflammatory response.

The classic signs of inflammation are heat, redness, swelling, pain, and loss of function. These are manifestations of the physiologic changes that occur during the inflammatory process. The three major components of this process are (1) changes in the caliber of blood vessels and the rate of blood flow through them (hemodynamic changes); (2) increased capillary permeability; and (3) leukocytic exudation.

Females with RA outnumber males by a 3:1 margin. To try and explain this discrepancy, researchers are investigating the role of female and male hormones and other possible gender-based differences in immune responses. The prevalence increases with age, approaching 5% in women over age 55. The onset of the disease in adults is usually between the ages of 40 to 60 years, although it can occur at any age. The disease is considered an autoimmune disease that is acquired and in which genetic factors appear to play a role. The evidence to support this theory comes from the presence of HLA-DR4 antibody (the B cell alloantigen) in 70 percent of patients with RA compared with 25% of unaffected controls (Stastny, p.869). There is an increased relative risk of four to five times, in the DR4-positive individual. "Local productions of rheumatoid factor (RF)-containing immune complexes that are capable of activating complement and attracting inflammatory cells also have been shown.

The inflammatory process is amplified by a variety of mediators including prostoglandins and a number of cytokines released by both synovial and infiltrating cells." (Wigley, p. 880) Rheumatoid Factor(s) (RF) are antibodies to IgG and are present in 60-80 percent of adults with the disease. (Immunoglobulin (Ig) is an antibody molecule. Higher vertebrates have five classes of immunoglobulin—IgA, IgD, IgE, IgG and IgM—each with a different role in the immune response.)

According to Weisman et al, at the Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles CA, "…emerging environmental hypothesis suggests that exposure to agents such as CO2, silica, asbestos, and cigarette smoke leads to increase levels of rheumatoid factor (RF), the hallmark antibody and most important prognostic marker for rheumatoid arthritis severity." Weisman and colleagues searched the medical literature, finding "that cigarette smoking appears to have an undesirable link to the pathogenesis of vascular disease of many types, including the possibility of a strong causal connection to rheumatoid vasculitis."

Features of Rheumatoid Arthritis

From the web page of University of Wisconsin Medical School


The etiology of RA remains unknown despite extensive study of metabolic and nutritional factors, the endocrine system, geographic, psychologic, and occupational data. It now appears that an unknown antigen initiates the autoimmune response resulting in RA. (Although the autoimmune disorders are considered acquired diseases, their causes usually cannot be determined.) This response supports the suspicion of an infectious origin of the disease process, which has included various bacteria and viruses, but without evidence of precipitating events. Even without this specific knowledge, treatment modalities have been developed that, while not curing the disease, can provide relief from the symptoms of the disease.

Scientists are now focusing on the idea that it is a T-cell-mediated autosomal (an autosome is any chromosome other than a sex chromosome) disease precipitated by both genetic and environmental factors. Being an autoimmune disease (see above) results in our own defenses aiding in the activation of the disease. The inflammation damages the synovial joints of the wrists, shoulders, knees, ankles and feet. Since rheumatoid arthritis is a systemic disease, it can attack other parts of the body besides joints. This may result in a general fatigue even though there are no specific complaints or the person may experience pathology of the nervous system, with accompanying sensory changes or sensory loss. Various lesions of the eye may occur, including some that are painful. Some patients may develop "dry eyes".

Bumps under the skin, called rheumatoid nodules, that often form close to the joints and other skin problems may develop in certain patients with the disease. The nodules develop in approximately 25 percent of the patients, usually those with the most rapidly progressive form of the disease. Those with nodules are likely to develop them in areas of the body where pressure is applied, like the sacrum and elbows. The patient's skin can also become fragile (easily torn) and bruise easily. Some people also experience the effects of RA in places other than the joints. Many people with RA develop anemia -- a decrease in the normal number of red blood cells. Very rarely, people may have inflammation of the blood vessels, the lining of the lungs, or the sac enclosing the heart.

In most cases of RA, the patient has remissions and exacerbations of the symptoms. This means that there are periods of time when the patient "feels good" and times when the patient "feels worse". There will likely be times that a patient with RA "feels cured". It is important to understand that there are very few patients that have complete remission of the disease and it is essential that the RA patient does not stop the treatment program established by knowledgeable health care practitioners. Rarely does the disease "go away", although at times the symptoms might temporarily remit.

Pathogenic events in rheumatoid arthritis

The attack on a joint by the disease usually begins with the synovium. The joint capsule is lined with a type of tissue called synovium, which produces synovial fluid. The synovial fluid secreted by the synovium is thought to serve two main purposes, lubrication of the joint and provision of nutrients to the avascular articular cartilage. Early in the disease, edema begins to be seen in cells in the synovium and multiplication of synovial lining cells occur.

White blood cells that are part of the normal immune system travel to the synovium and cause a reaction. This reaction, or inflammation, is called synovitis, and it results in the warmth, redness, swelling, and pain that are typical symptoms of RA. During the inflammation process, the cells of the synovium grow and divide abnormally, making the normally thin synovium thick and resulting in a joint that is swollen and puffy to the touch.

As the disease progresses, the synovium may grow considerably larger eventually forming tissue called pannus. The pannus is a sheet of inflammatory granulation tissue that spreads from the synovial membrane and invades the joint in rheumatoid arthritis ultimately leading to fibrous ankylosis. Pannus can be considered the most destructive element affecting joints in the patient with rheumatoid arthritis. Pannus can attack articular cartilage and destroy it. Further, pannus can destroy the soft subchondral bone once the protective articular cartilage is gone. There is chronic inflammation with lymphocytes and plasma cells that produce the blue areas beneath the nodular proliferations.

In this disease process, an interaction between antibodies and antigens occurs, and causes alterations in the composition of the synovial fluid. Ultimately, digestants are formed in the fluid that attacks the surrounding tissue. Once the composition of this fluid is altered, it is less able to perform the normal functions noted above, and more likely to become destructive

The changes in the synovium and synovial fluid are responsible for a large amount of joint and soft tissue destruction. The destruction of bone eventually leads to laxity in tendons and ligaments. Under the strain of daily activities and other forces, these alterations in bone and joint structure result in the deformities frequently seen in patients with rheumatoid arthritis. Considerable destruction of the joint can occur with pannus (synovial lining cell proliferation, see above) invading the subchondral bone.

Bone destruction occurs at areas where the hyaline cartilage and the synovial lining do not adequately cover the bone. If the disease progresses to a more advanced stage, the articular cartilage may lose its structure and density resulting in an inability to withstand the normal forces placed on the joint. In these advanced cases, muscle activity causes the involved ends of the bones to be compressed together causing further bone destruction. Further, the disease can irreversibly change the structure and function of a joint to the degree that other degenerative changes may occur, especially in the weight bearing joints of the body. Thus, joint destruction can progress to the degree that joint motion is significantly limited and joints can become markedly unstable.

Overview of Pathogenic Events in Rheumatoid Arthritis

Initiation Antigen presentation

Immune response triggering

Macrophages/dendritic cells


No symptoms

Morning stiffness, swelling/redness

Early Inflammation Accumulation in synovium

Iterferon-? production

Interleukin-1/TNF-a secretion

Expression of adhesion molecules

Transdermal migration

Cell activation

Releasing of degrading molecules

B/T cells

T cells


Endothelial cells

T cells

Synoviocytes (synovial lining cells) Synoviocytes

Irreversible degradation Pannus formation




Bone and cartilage destruction

The above chart is taken from VanderBorght A et al. Semin Arthritis Rheum 2001; 31: 160-175.



Albano S, Santana-Sahagan E, Weisman MH. Cigarette Smoking and Rheumatoid Arthritis. Semin Arthritis Rheum 2001; 31:146-159.

Goldenberg, Marvin M. (Mount Sinai Medical Center Health System). Entanercept, A Novel Drug for Treatment of Patients with Severe, Active Rheumatoid Arthritis. Chemical Therapeutics 1999; (21):75-87.

Harris EJ. Rheumatoid Arthritis. Philadelphia, WB Saunders, 1997

Jensen M, Turner J, Romano J, Karoly P. (1991) Coping with chronic pain: a critical review of the literature Pain 1991; 47:249-283)

Lambert VA, Lambert CE, Kipple GL, Mewshaw EA. Relationship among hardiness, social support, severity of illness and psychological well being and depression in women with RA. Health Care Women Int 1990; 11:159-173).

Smolen JS, Tohidast-Akrap M, Gal A, Kunaver M, Ederl G, Zenz P, et al. The role of lymphocytes and cytokines in rheumatoid arthritis. Scand J Rheumatol 1996; 25:1-4.

Stastny P. Association of the B-cell alloantigen DRW4 with rheumatoid arthritis. N Engl J Med 1978; 298:869.

Wigley FM. Rheumatoid Arthritis In: Barker LR, Burton JR, Zieve PD. (Eds.) Principles of Ambulatory Medicine, 3rd. Ed, Baltimore, Williams & Wilkins 1991, p. 880.



See: Rheumatoid Arthritis Part I-General Overview-
See: Rheumatoid Arthritis Part II-TNF and Enbrel
See: Rheumatoid Arthritis-Part III-Vioxx, Celebrex and the Elderly Who Have Ulcers

Harold Rubin, MS, ABD, CRC, Guest Lecturer
updated July 6/ 2010

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