Nonconventional Therapy for Arthritis
June 12, 2000
Nonconventional Therapy for Arthritis
Author: Bernard R. Rubin, DO, FACP, Professor, Department of Internal Medicine; Chief, Division of Rheumatology, Texas College of Osteopathic Medicine, Fort Worth, Texas.
Peer Reviewers: Robert Hawkins, MD, FACR, Associate Program Director, Internal Medicine Residency Program, Kettering Medical Center, Kettering, Ohio; and Thomas W. Henderson, MD, Medical Director, Kettering Arthritis Center, Kettering, Ohio.
Editor’s Note—"I didn’t say it was good for you," the king replied. "I said there was nothing like it."—Lewis Carroll, Through the Looking Glass. Why is there such an explosion in current American culture for the use of complementary or alternative therapies as a treatment for arthritic disease? Many patients suffering from chronic diseases such as rheumatoid arthritis, osteoarthritis, and other musculoskeletal diseases are willing to try any new treatment option that might offer them some symptomatic benefit. Patients are often fearful of the well-publicized toxicities of traditional antirheumatic drug therapy, and they certainly have the perception that alternative therapy is "safer." Reasons that patients may seek to use alternative arthritic treatments include dissatisfaction with conventional treatment because it has either been ineffective,1 caused adverse events,2 or is too costly.3 Patients also seek alternative therapies because there is a feeling that they have more control and personal autonomy over these treatments and thereby give them additional control over their health care decisions.4 Finally, alternative therapies may seem more attractive because patients may feel that they fit better with their own philosophy or beliefs regarding the nature of health and disease.5 A recent study suggests that the most influential factor in people’s decisions to use alternative health care may be its perceived efficacy.6 Not only do patients want potentially more effective alternatives than the drugs that traditional medicine offers for the treatment of rheumatic diseases, but they also want cheaper and simpler alternatives. Until the recent advent of some refreshing new therapies for rheumatic diseases, including COX-2 specific inhibitors and biological agents for the treatments of various rheumatic diseases,7 the therapy for many rheumatic diseases over the past decade had not been associated with the advances in therapy of AIDS, heart disease, and cancer. What I propose to discuss specifically in this paper are the nutritional and dietary supplements that have been widely promoted as treatment for arthritic diseases, as noted in Table 1.
Therapeutic touch, manual medicine, and mind-body medicine are beyond the scope of this review. In 1993, Eisenberg et al published results of a national telephone survey performed with adults across the United States.8 Thirty-four percent of the individuals surveyed had used at least one complementary or alternative modality or remedy in 1990. Another survey from California by Cronan et al noted that 84% of the patients who had self-reported osteoarthritis or rheumatoid arthritis had used a complementary alternative medical treatment during the preceding six months.9 Gordon et al surveyed primary care physicians in the Kaiser Permanente Medical Care Program of Northern California and found that 89% of the adult primary care physicians and obstetricians had either used or recommended to patients a complementary or alternative medical practice during the previous 12 months.10 It was also interesting to note that in the same study, 40% of those physicians were motivated by uncontrolled observations, whereas only 5% were motivated by articles they had read in professional journals.
The U.S. population is spending almost $14 billion per year on alternative medical therapies.8 Clearly, the use of complementary alternative medications by sufferers of arthritic diseases is prevalent. Evidence would suggest that the use of these alternative therapies is becoming increasingly popular, if one can judge by the frequent articles in the lay press and the amount of shelf space given to dietary nutritional supplements in grocery stores, pharmacies, and health food stores. Therefore, it is important for primary care practitioners to be familiar with some of the alternative therapies that their patients may be taking so that they might have some insight into the nature of these preparations. Although many patients add nutritional or vitamin supplements to conventional therapy, what is particularly worrisome is when patients stop physician-prescribed treatments and substitute alternative supplements instead. Additionally, there needs to be concern about supplements adversely interacting with prescription medications.
What constitutes a complementary alternative therapy? Therapy may be safe, unsafe, or have questionable safety and efficacy. As physicians, we should evaluate the alternative therapies in a scientific, evidence-based manner. This will be the method that I will use to evaluate each of the topics to be discussed.
| Table 1. Nonconventional Therapies for Arthritis |
| • Fish Oil |
| • Glucosamine |
| • Chondroitin |
| • Ginger |
| • Shark Cartilage |
| • Collagen |
| • DHEA |
| • Copper |
| • Selenium |
Dietary Fatty Acids
These supplements have been one of the most extensively studied neutraceuticals. Dietary fatty acids were proposed as a way to modulate the inflammatory response in patients with rheumatic diseases. The rationale is that dietary fatty acids, such as omega-3 polyunsaturated fatty acids that are found in cold-water fish, may suppress or shift to less inflammatory prostaglandin production and leukotriene synthesis. This type of an anti-inflammatory response is similar to the one achieved with nonsteroidal anti-inflammatory drugs (NSAIDs) and some of the other anti-inflammatory therapies in rheumatic disease. Therefore, the use of omega-3 polyunsaturated fatty acids was felt to represent a "natural" anti-inflammatory dietary compound.11 Botanical polyunsaturated fatty acids such as evening primrose oil and flaxseed plants have also shown to be anti-inflammatory in experimental animal models. The clinical usefulness of fish oils or plant-derived fatty acids in the treatment of arthritic diseases in humans is still not clear because there is uncertainty as to which components of these oils might be the most effective, what dose is appropriate, what the duration of therapy should be, and which patients would be most appropriate for treatment. Controlled trials of fish and plant oil for patients who had rheumatic diseases have shown that fish oil improved symptoms of psoriatic arthritis and rheumatoid arthritis, but not those of osteoarthritis.12-14
Many of these studies were double-blind, placebo-controlled studies where the duration of fish oil supplementation varied from 12 to 52 weeks. In addition, the total amount of fish oil that was ingested daily varied from 1 to 7 g. The outcome measures in most studies included patient or physician global assessment of disease activity, the number of tender or swollen joints, grip strength, and the duration of morning stiffness. Decreased joint tenderness is often the most common favorable outcome reported, with the average improvement up to about 30%, an amount similar to what is expected from placebo. In studies where patients were allowed to continue NSAIDs, use of these medications tended to significantly decrease while patients were taking supplemental fish oils.15 A meta-analysis of 10 studies with fish oil has been reported.16 Twelve weeks of fish oil supplementation was chosen as the common time in all studies for this analysis. Results indicated that there were statistically significant improvements at 12 weeks for tender joint count and duration of morning stiffness in fish-oil-treated groups or when compared to placebo. Fish oil supplementation was shown to significantly reduce tender joint count and duration of morning stiffness, but no other improvement in outcome measures reached significance.
Overall, dietary fish oil supplementation showed a modest beneficial effect in the treatment of rheumatoid arthritis patients in all of these studies. In all of the cases reviewed in the analysis, NSAIDs and disease-modifying antirheumatic drugs were continued throughout the trial period. Therefore, any benefit from fish oil therapy was over and above the benefit that was already being obtained from traditional therapy.
Linoleic acid is present in polyunsaturated vegetable oil such as soybean, corn, cottonseed, sunflower, and safflower oils. Currently, diets high in linoleic acid content are thought to be healthier and therefore are widely used by individuals in the United States and western Europe. Less than 50% of the studies in the analysis included dietary advice about maintaining fat intake or urging patients to continue their usual dietary habits. Linoleic acid and omega-3 fatty acids are actually antagonists at several levels of interaction. Some animal studies have indicated that linoleic acid diets may have a beneficial effect in inflammatory disorders that have been experimentally induced or that occur spontaneously.17 There is no evidence of any direct effect between rheumatoid arthritis activity and linoleic acid intake or diets common in western society. In fact, dietary fish oil has a greater fatty-acid-lowering effect when linoleic acid intake is decreased. Therefore, a diet high in linoleic acid could suppress the anti-inflammatory effect of the omega-3 fatty acids used in these studies of rheumatoid arthritis patients.18
Some rheumatologists have noted the usefulness of fish oil therapy for patients who have been unwilling or unable to take NSAIDs. This would include patients with serious ongoing gastrointestinal disorders, renal insufficiency, or those who desire "natural" rather than "drug therapy."19 One problem with fish oil therapy is that most of the studies used the treatment with 4-6 g of fish oil daily. This dose requires a large number of capsules and an obvious expense that many patients cannot sustain.
Glucosamine
Glucosamine and chondroitin have been highly touted in the lay press recently as "cures" for arthritis. Glucosamine has been studied as therapy for osteoarthritis for decades. Glucosamine and chondroitin have received publicity as natural remedies for osteoarthritis. Glucosamine is derived from the shells of crustaceans. Chondroitin, which is a component of connective tissue, is extracted from cows’ tracheas. There is debate concerning whether the combination is more effective than either agent by itself. There have been several recent studies evaluating the efficacy of glucosamine sulfate in the treatment of osteoarthritis. A randomized, double-blind, parallel-group study of glucosamine sulfate 500 mg t.i.d. vs. ibuprofen 800 mg t.i.d. orally for four weeks was undertaken. Two hundred patients were enrolled, with the majority of patients between the ages of 50 and 65 years of age. Most of the subjects had bilateral knee involvement and symptoms that had been present for an average of five years. Clinical improvement tended to occur sooner in the ibuprofen-treated group than in the glucosamine sulfate group, but there was no difference between the groups from the second week through completion of the study.20 Another randomized, double-blind, placebo-controlled, crossover trial was done by Leffler et al.21 In this study, after a three-week baseline period, subjects were randomly assigned to receive either a combination of glucosamine hydrochlorate 1500 mg per day plus chondroitin sulfate 1200 mg per day plus magnamese ascorbate 228 mg per day or placebo capsules for eight weeks. For an additional eight weeks, patients were crossed over to the regimen that they had not previously taken. Patients were not permitted to take NSAIDs but were allowed to take acetaminophen for pain. Patients with osteoarthritis of both the knee and the back participated in this study. In general, patients with knee osteoarthritis showed some improvement but there was no effect on osteoarthritis of the spine. About 50% of the patients with osteoarthritis of the knee showed some improvement compared to placebo, although the degree of improvement was modest.
In June 1998, the National Institute of Arthritis and Musculoskeletal and Skin Diseases issued a request for proposals to study the efficacy of glucosamine and glucosamine-chondroitin sulfate combinations in the treatment of osteoarthritis of the knee. An award was made in September 1999. Hopefully, well-controlled trials of these agents will be conducted and will provide useful clinical information. Glucosamine is an aminomonosaccharide and is a constituent of glycoprotein, proteoglycans, and glycosaminoglycans (see Figure 1).
It is found in articular cartilage and therefore could be appropriate therapy for osteoarthritis. In this condition, the production of proteoglycans is defective and there is a net loss within the cartilage.22 We recently completed a placebo-controlled, double-blind pilot study of a glucosamine preparation in which we showed a trend toward symptomatic improvement in patients with osteoarthritis of the knee.23 Three functional measurements of osteoarthritis severity included the osteoarthritis severity index, physician’s global assessment, and patient’s global assessment; all improved over a six-week time period in glucosamine-treated patients compared to placebo.
Recently, a large, double-blind, placebo-controlled trial of glucosamine sulfate demonstrated that it may not only be useful for relieving the symptoms of osteoarthritis, but suggested that there was a lack of progression of x-ray involvement of the knees in patients who were treated with 1500 mg of glucosamine sulfate daily over the two years of the study.24 In Europe, glucosamine is classified as a slow-acting anti-rheumatic drug.
In both Germany and Russia, glucosamine is one of the mainstays for the treatment of osteoarthritis.25 In these countries, the recommended dose of glucosamine is 500 mg three times a day for 6-8 weeks and then twice a day thereafter. Low-dose NSAIDs are also used for flares of osteoarthritis in conjunction with 500 mg of glucosamine once a day. Anecdotally, the use of glucosamine may allow patients to decrease the amount of NSAIDs necessary to control their osteoarthritic pain. Glucosamine is currently the most widely used dietary supplement for the treatment of arthritis probably, in part, due to the publication of a book called The Arthritis Cure in which the use of glucosamine and chondroitin was touted.26
A problem with glucosamine and, in fact, all other supplements discussed in this paper is the fact that there are significant unknowns regarding the safety and the consistency of the compounds available as dietary supplements in the United States. The Dietary Supplements Health and Education Act of 1994 allows glucosamine to be sold without any testing for efficacy, safety, or manufacturing standards. There are few data about the purity of supplements and, in fact, there are no data about any batch-to-batch variation in the quality of glucosamine available. If one makes recommendations regarding the potential use of dietary supplements, it is difficult to recommend a specific brand. In fact, it is difficult to assure a patient that the same brand of supplement will be equally efficacious over a long period.
Although in general glucosamine and chondroitin are relatively safe, there have been gastrointestinal side effects reported, such as pyrosis, diarrhea, nausea, and vomiting. There are reports suggesting a possible link between glucosamine and increased insulin resistance. This effect of insulin resistance has been demonstrated with continuous intravenous infusion of glucosamine in animals who are normoglycemic but not hyperglycemic. The potential for problems in humans must be monitored.27 Isolated, anecdotal reports of insulin resistance in patients with type II diabetes treated with oral agents have also been noted. In addition, chondroitin sulfate has a chemical structure that resembles heparin. Studies in dogs using the combination of glucosamine and chondroitin sulfate have shown minor decreases in white blood cell counts and decreases in platelet counts and platelet aggregation but no change in bleeding time or clotting times.28
Delafuente has recently reviewed several published studies using glucosamine in the treatment of osteoarthritis and has found methodological flaws in many of them.29 In some of these older studies, he reports that compliance data are not included, diagnostic criteria for patient selection were not clearly stated, concomitant treatments for osteoarthritis prior to entering the study were not clearly stated, and the wash-out period was not defined. Overall, the small numbers of patients included in many of the studies, combined with a lack of rigorous classification of osteoarthritis, has contributed to the confusion in the medical literature regarding the efficacy of these compounds. It is hoped that more studies like the placebo-controlled, double-blind studies cited earlier will be more helpful in answering the definitive questions regarding long-term efficacy and safety for glucosamine and chondroitin sulfate.
Ginger
Ginger has been used for the treatment of inflammation and rheumatism. One proposed mechanism of action is related to the inhibition of leukotriene or prostaglandin synthesis, although these ideas are from basic science studies.
A small open trial of patients with both osteoarthritis and muscular discomfort evaluated powdered ginger supplementation. Seventy-five percent of the patients with osteoarthritis and all of the patients with muscular discomfort experienced pain relief to some degree with no adverse side affects.30 However, once again these results must be viewed cautiously because the criteria for the diagnosis of arthritis were loose and the way "relief" was quantified was not validated.
Shark Cartilage and Collagen
Reportedly, shark cartilage is of value in the treatment of chronic arthritic disorders. The data are anecdotal and lack controlled studies. On the other hand, there have been multiple double-blind, placebo-controlled trials of collagen type II (COL II) in patients with arthritis. This is a research-grade, purified product that is not readily commercially available. Trentham et al performed a placebo-controlled, double-blind study of COL II derived from chickens in patients who had active rheumatoid arthritis.31 Significant improvement in painful and swollen joints was noted in the small patient group receiving the collagen. Subsequently, a larger study done with more than 270 patients with active rheumatoid arthritis demonstrated positive effects even at the lowest dose of COL II used in this 24-week study.32 Further studies are needed to confirm these results.
DHEA
Autoimmune diseases and, specifically, rheumatoid arthritis and systemic erythematosus are more common in women than men.33 Dehydroepiandrosterone (DHEA) is produced by the adrenal gland. DHEA is produced from cholesterol and is primarily metabolized into testosterone and estrogens (see Figure 2).
During periods of stress, there is a shift in the pregnenolone metabolism away from the production of DHEA to the production of glucocorticoids, which are also produced by the adrenal gland.34 Production of DHEA peaks at around age 25 and then declines. There is research evidence that DHEA has an effect on the immune system functions—specifically, interleukin-2 production.35 Studies with small numbers of patients have looked at the usefulness of supplemental DHEA and the results have been variable. A study with a few rheumatoid arthritis patients showed no benefit, and others in patients with systemic lupus erythematosus showed a mild decrease in clinical activity. A pilot study using DHEA for the treatment of chronic fatigue syndrome also tended to yield some positive clinical results.36-38 DHEA supplementation can have side effects. Side effects noted in studies done to date, as well as in the clinical use of this supplement, have included prostate enlargement in men, acneiform dermatitis, and gastrointestinal upset. Other potential side effects include liver damage, masculinization of women, and insulin resistance.39 Therefore, DHEA should be taken with caution as a dietary supplement. The long-term consequences of treatment with DHEA in persons with autoimmune disease or other rheumatic diseases is unknown.
Trace Elements
There is interest in the nutritional status of patients with rheumatoid arthritis regarding levels of trace elements, such as zinc, selenium, copper, and magnesium. These trace elements are cofactors in metabolic processes that involve immune system or collagen function in the body.40 Although there is certainly a physiological role for trace elements in the body, the therapeutic usefulness of supplementing persons with these compounds who have chronic or inflammatory diseases is open to question. Copper bracelets are commonly used by patients who have arthritis. The role of copper in inflammatory processes is unclear despite the fact that levels of copper and ceruloplasmin, to which copper is bound in the body, may positively correlate with levels of tumor necrosis factor (TNF) and certain interleukins in the body.41 Interestingly, copper complexes of NSAIDs have been demonstrated to be more active than NSAIDs alone. One study in humans using a copper salicylate applied topically yielded higher plasma salicylate levels than with the equivalent amount of medication without copper. The importance of this is unknown.42 This study also evaluated the use of copper bracelets and demonstrated a significant improvement in patients who wore copper bracelets vs. aluminum bracelets. Copper will dissolve in human sweat, which raises questions as to whether the beneficial effect of wearing copper bracelets may be due to transport of the copper through the skin.
Selenium has been suggested to have anti-inflammatory, antiproliferative, and immunomodulatory effects. The role of selenium has been studied for more than 20 years. Selenium is involved with the enzyme glutathione peroxidase, which detoxifies free radicals and other damaging oxygen derivatives. Selenium deficiency may reduce the ability of T- and B-cells to proliferate in response to stimulation, whereas selenium supplementation may increase these responses. Interestingly, selenium may be an immunostimulant in low doses, whereas it may be immunosuppressive when given in high doses.
Interestingly, most studies of selenium were done in Europe, where until 1984 the selenium levels of the entire population were low until it was added to soil fertilizers in 1984.43 Even given the fact that there may have been a selenium deficiency in the population, in most studies of rheumatoid arthritis patients, selenium levels were lower than in healthy controls. Most of these were small, uncontrolled studies. In addition, rheumatoid arthritis patients who were supplemented with selenium did not improve their health status, even when a selenium deficiency that had been detected was corrected.44 Peretz has reported a 40% improvement in a small group of rheumatoid arthritis patients given several different types of selenium supplements.45
Selenium concentrations have been found to be relatively low in patients with rheumatoid arthritis compared to healthy controls. Studies have demonstrated inconclusive results with regard to selenium supplementation in rheumatoid arthritis. Some studies have demonstrated clinical improvement with sodium selenite supplementation, whereas double-blind, placebo-controlled studies have not demonstrated any clinical differences. Other studies of selenium supplementation in rheumatoid arthritis patients yielded minimal clinical differences at four months, but after eight months of supplementation, significant differences in grip strength, morning stiffness, and articular pain were noted.46,47 The value of selenium supplementation is unclear. It may act to stimulate pre-existing defense mechanisms and could be affected by other disease-modifying drugs such as d-penicillamine, gold compounds, or corticosteroids.
Summary
Patients with chronic diseases are making choices every day between quality of life and the potential side effects of medications offered for treatments. Patients are urged to take a more active role in their overall health care and they are constantly being bombarded by advertisements for health foods, dietary aids, and vitamin supplements claiming to offer the chance of decreased arthritis pain with minimal drug side effects. Patients are reticent to discuss alternative medical treatment with their doctors. This has not changed in the past decade.8 At least every month, there is an article in Arthritis Today (a publication by the Arthritis Foundation for its members) that discusses a different alternative or complementary therapy. Rheumatologists and other physicians caring for patients with arthritis are often unaware of the newest or current fad "treatment for arthritis." This reinforces the perception among patients that physicians who practice traditional medical care are out of touch with the current popular treatments for arthritis. Since rheumatologists can’t offer a cure for any of these diseases that we treat, it must be understood that patients are going to seek out alternative treatment options on their own. A recent study published by Mikuls et al has shown that dietary supplement use increases with higher levels of education and patients and physicians rarely discuss the use of these agents.48 Physicians must inquire about the use of dietary supplements in their patients who have rheumatic diseases because there may be potential toxicities or drug interactions that could occur. It is also important for physicians to promote good clinical research to evaluate dietary supplements—both for their efficacy and their effects on the natural history of rheumatic diseases. It is clear that not all that is "natural" is safe, and the use of these dietary and nutritional supplements is becoming more extensive. Physicians, by discussing and acknowledging the use of dietary supplements and other complementary treatments for arthritis, promote the doctor-patient relationship and may improve patient satisfaction and possibly clinical outcomes.
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