Current Rheumatology Reviews - Volume 5, Issue 4, 2009

Not a day goes by, in my practice, without a patient asking me about a nutritional supplement or an alternative medical therapy in the treatment of their rheumatic diseases. Several published studies have shown that a majority of rheumatic disease patients use alternative therapies in their treatment regimen. As rheumatologists, we deal with patients who have chronic conditions, often painful, and our therapies seldom completely address their pain completely or sometimes even cause significant side effects. Additionally, as sufferers of chronic diseases, our patients live with a reality that something could go wrong at any time. They seek solace and comfort from their physicians in helping them deal with their problems. Unfortunately, due to the immense pressures of time, economy and academic commitments, we as physicians are not able to provide this comfort to the patients in a meaningful or consistent way. It is in this space that a whole industry of alternative therapies has been established and currently flourishes. However, as advocates for our patients, it is important for us to be able to guide our patients to those therapies that work and steer them away from those that may harm them. As our patients have become more sophisticated in their use of the internet, so has their exposure to a wide variety of claims, often times dubious, about great cures for their chronic conditions. Thus, it is important for our field to investigate those alternative therapies and non-pharmacologic treatments that have merit. It is also important for us to acknowledge those therapies which have some merit when examined scientifically. In this current issue of the journal, we have two outstanding guest editors who have helped synthesize the current state of knowledge in specific topics that fall under the purview of Complementary and Alternative Medicine. Dr. Jiman He and colleagues provide evidence based systematic reviews and meta-analysis of exercise and complementary and alternative therapies for rheumatic conditions. Dr. Masuko and his colleagues present reviews of the current state of knowledge about nutritional substances and their relationship to arthritis. These articles are important reading for rheumatologists as they give us a sense of the current state of the field and allow us to answer the questions our patients have in a meaningful manner that is based on science.

Pain is the most common symptom of rheumatic diseases. Uncontrolled pain has a universal and profoundly negative effect on quality of life. There are still many unanswered questions for researchers to explore. Currently, pharmacological analgesics remain the major therapy. However, such analgesics have well-known side-effects. Various nonpharmacological approaches have been widely used as complementary therapies in management of rheumatic pain. These include acupuncture, massage, exercise, electrical stimulation, cryoanalgesia, music therapy, and etc. A recent survey in the United States showed that almost half of osteoarthritis sufferers reported using at least one type of complementary therapy during the 20 weeks prior to the survey. Many rheumatology patients use non-pharmacological therapies, emphasizing the significance of such approaches to pain management. The importance of such therapies could be enhanced if obstacles to their use were overcome, and doubts about therapeutic efficacies dispelled. Nonpharmacological therapies are potentially of great clinical use; the task facing scientists and clinicians is heavy. The mechanisms of action of such therapies, their efficacies in pain reduction, and potential adverse effects, need to be elucidated. Also, it is necessary to explore which method works best for any particular rheumatic condition. When even some of these questions are further understood, you will truly have a Hot Topic issue to review. Jiman

Objective: To systematically review the efficacy of exercise interventions on pain relief in patients with fibromyalgia (FM). Methods: We performed a comprehensive search of 8 western databases and reference lists through March 2009. We included randomized controlled trials (RCTs) with pain as an endpoint, measured by the Fibromyalgia Impact Questionnaire (FIQ) or a visual analogue scale (VAS). The exercise treatments were compared with a no-exercise control group. Study quality was assessed by the Jadad scale. We calculated effect sizes to assess the magnitude of treatment effect, and meta-analyzed for overall effect. Results: Forty-five studies were critically appraised for effects on pain. Ten RCTs published between 1992 and 2008, conducted in Europe and North America met eligibility criteria with 767 participants (98% women). Mean age was 47 years and mean symptom duration was 10 years. The meta-analysis results showed that 6 to 24 weeks of aerobic, strength training, pool and multi-component exercise had a statistically significant decrease in pain outcomes versus education, usual care and non-exercise controls. The pooled effect size was 0.45 (95% Confidence Interval, 0.09 to 0.80). Conclusion: Physical exercise may have positive effects on pain reduction in patients with FM. Long-term, rigorous and well-controlled randomized trials are warranted.

Rheumatic disease pain is an important health concern that causes significant distress and functional impairment to many patients. While standard pharmacological treatments with analgesics, antidepressants, and anticonvulsants can provide substantial relief, an increasing proportion of patients are seeking an integrated approach to pain management involving both pharmacological and non-pharmacological treatments. Complementary and alternative medical (CAM) techniques, such as thermotherapy, cryotherapy, acupuncture, massage, and spinal manipulation, are commonly employed by patients with rheumatic disease pain. We review the evidence supporting the use of CAM in the treatment of rheumatic disease pain and address the major challenges hindering further proliferation of these techniques. Our analysis supports further investment into basic research and clinical studies on the mechanisms of action and clinical effectiveness of CAM. We also propose steps to incorporate CAM into the evidence-based framework of conventional medicine.

Non-pharmacologic treatments (NPT) for patients with rheumatologic disease aim to enhance overall health and bodily function. This chapter reviews exercise (including hydrotherapy and balneotherapy), acupuncture, manipulation, massage, and assistive devices as adjunct therapy for different painful diseases including rheumatoid arthritis and fibromyalgia. While some NPTs are justified through numerous studies, others may lack evidence. The most studied non-pharmacologic treatment is exercise. Patients with osteoarthritis, rheumatoid arthritis, fibromyalgia, SLE, and Sjogren's all receive benefit from exercise. Acupuncture is one of the oldest non-pharmacologic treatments, but randomized controlled trials supporting its efficacy are generally lacking. The art of manipulation is practiced by osteopathic physicians and chiropractors. Literature supporting manipulation is also sparse but patient satisfaction remains high. Other treatments such as massage and assistive devices lack consistant evidence. This chapter hopefully proves that exercise is a vital treatment in all rheumatologic and painful conditions and other non-pharmacologic treatments need further research study.

Osteoarthritis of the knee is a major cause of disability among adults worldwide. Important treatment options include nonpharmacologic therapies, and especially symptom management strategies in which patients take an active role. Among these, mind-body therapies may have particular promise for alleviating the distressful symptoms associated with osteoarthritis of the knee. However, systematic reviews are lacking. The objective of this paper is to review Englishlanguage articles describing clinical studies evaluating the effects of patient-driven mind-body therapies on symptoms of knee osteoarthritis. Eight studies, representing a total of 267 participants, met the inclusion criteria. Interventions included tai chi, qigong, and yoga. Collectively, these studies suggest that specific mind-body practices may help alleviate pain and enhance physical function in adults suffering from osteoarthritis of the knee. However, sample sizes are small, rigorous investigations are few, and the potential benefits of several mind-body therapies have not yet been systematically tested. Additional high-quality studies are needed to clarify the effects of specific mind-body therapies on standardized measures of pain, physical function, and related indices in persons with osteoarthritis of the knee, and to investigate possible underlying mechanisms.

Many studies have suggested that metabolic or nutritional factors such as lipids [1, 2], vitamins [3, 4], and glucose [5] may contribute to the pathogenesis of arthritic diseases; however, this is a controversial topic [6-9]. The current “hot topic” of Current Rheumatology Reviews has been selected with the intent of providing readers with a recent overview of the topics pertaining to the implications of nutritional factors in arthritis and to evoke active discussion about the basic and clinical implications of the daily diet in the arthritic condition. In particular, studies have suggested that fatty acids (reviewed by Calder); amino acids (Yoneda et al.); green tea-derived polyphenols (Ahmed); and hydrocarbons in cigarettes, grilled meats, and industrial by-products (Uno et al.) may modulate the immune or inflammatory status. The Mediterranean diet may be beneficial in reducing arthritic symptoms (Oliviero et al.), and dietary supplements, often used by patients to correct a potential nutritional imbalance, may also play a role in this process (Ikuyama et al.). These phenomena, at least in part, may be due to the effect of adipokines (Gabay et al.), and nutritional elements may directly modulate genetic or molecular expression by activating nuclear receptors (Murata et al.). It should be noted that the clinical significance of these nutritional interventions has not been corroborated with sufficient evidence, and established anti-rheumatic or anti-inflammatory therapies that use disease-modifying anti-rheumatic drugs (DMARDs) or biologics (e.g., anti-tumour necrosis factor [TNF] agents) are still the first-line therapies. For example, the ingestion of dietary supplements is not a substitute for a prescription of methotrexate. Nevertheless, dietary or nutritional elements are also taken daily (usually t.i.d., and probably easier to remember than taking synthetic drugs); therefore, it is necessary to determine the manner in which these elements adjust the body homeostasis and anabolism in conjunction with the other administered drugs. Rheumatologists, other medical professionals, and patients themselves should be aware of the substances that are ingested by a patient, and regulating the fine nutritional milieu that surrounds inflamed joints may provide another (not always apparent but important) beneficial effect to the overall outcome. Thus, nutrition, a classic factor, may be developed as the latest basic support for antiarthritic therapy.

The fatty acids of most relevance to inflammatory processes are the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid, the precursor of inflammatory eicosanoids like prostaglandin E2 and leukotriene B4, and the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are found in oily fish and fish oils. Eicosanoids derived from the n-6 PUFA arachidonic acid play a role in rheumatoid arthritis (RA), and the efficacy of nonsteroidal antiinflammatory drugs in RA indicates the importance of pro-inflammatory cyclooxygenase pathway products of arachidonic acid in the pathophysiology of the disease. EPA and DHA inhibit arachidonic acid metabolism to inflammatory eicosanoids. EPA gives rise to eicosanoid mediators that are less inflammatory than those produced from arachidonic acid and both EPA and DHA give rise to resolvins that are anti-inflammatory and inflammation resolving. N- 3 PUFAs exert effects on other aspects of immunity relevant to RA like leukocyte chemotaxis, antigen presentation, T cell reactivity and inflammatory cytokine production. Fish oil has been shown to slow the development of arthritis in an animal model and to reduce disease severity. Randomised clinical trials have demonstrated a range of clinical benefits of fish oil in patients with RA including reducing pain, duration of morning stiffness and use of non-steroidal antiinflammatory drugs.

Along with its capacity to store energy, the white adipose tissue is a source of cytokines, called “adipocytokines” or “adipokines”, acting by paracrine, autocrine and systemic pathways. However, it is noteworthy that the source of these adipokines in physiological and/or pathological conditions is not restricted to the adipose tissue. The modulation of immunological and inflammatory pathways by adipokines has been extensively studied in the last ten years. This systematic literature review focuses on the role of leptin, adiponectin, resistin and visfatin in arthritis. Although their roles need to be clarified, these adipokines will soon be pivotal to the diagnosis, the prognosis and the pharmacological approaches of rheumatoid arthritis and osteoarthritis.

The present paper reviews the main aspects of the health properties of Mediterranean food pattern and its components with particular regard to rheumatoid arthritis. The Mediterranean diet is based on a pattern of eating closely tied to the Mediterranean region and is characterized by an abundance of foods from plant sources, limited meat consumption, moderate amounts of fish, moderate consumption of wine and extravirgin olive oil as the main source of fat. The Mediterranean food pattern has shown a number of beneficial and healthy effects not only in preventing cardiovascular diseases and cancer, but also diabetes, metabolic syndrome, visceral obesity and arthritis. Most of these effects are related to the consumption of extravirgin olive oil which, with its high content of MUFA and non-fat microcomponents such as phenolic compounds, squalene and oleocanthal, has demonstrated important antiinflammatory effects both in vitro and in vivo. Biologic response modifiers, such as TNF-alfa blockers, have set new therapeutic standards for the treatment of RA. On the other hand diet may represent a valuable support to the pharmacological treatment in rheumatoid arthritis.

Dietary supplements are the most popular class of complementary and alternative medicine (CAM) in Japan. In the present review, we describe several characteristics of dietary supplement users in patients with RA in Japan, based on our recent survey. Sixty percent of RA patients used supplements. Prevalence was higher in female than in male patients, and users were younger than non-users, particularly among females. These features were those found in CAM users in general. In comparison with CAM users with cancer, several specific characteristics of RA users emerged. First, the proportion of current users was significantly higher among those who had been diagnosed within the last 5 years compared with those who had been diagnosed more than 5 years ago, indicating that patients in the early years of disease were likely to use supplements. Second, RA patients preferred products made from herbs, algae or components of cartilage. This preference was different from that of cancer patients, who predominantly used mushroom-based products. Third, users expected CAM to produce ‘alleviation of symptoms’ and ‘health promotion’, indicating that the users' expectations were essentially ‘complementary’. In contrast, cancer patients expected more positive and direct disease outcomes. Finally, we propose some ideas regarding the clinical significance of future dietary supplement use in RA, as orthodox therapeutic modalities greatly expand.

Members of the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors are key regulators of glucose and lipid metabolism. Recent studies have demonstrated that PPAR activation plays an important role in inflammatory arthritis. A variety of natural ligands including nutritional elements are known to activate PPARs, suggesting the contribution of dietary nutrients to the regulation of PPAR-mediated gene transcription in the nucleus. This mini-review introduces some aspects of the potential role of these nutrients in modulating the pathophysiology of arthritis through PPAR signalling.

Amino acids are not only the building blocks of proteins but are also key regulators of various pathological and physiological processes, including immune responses, in living cells. However, the mechanisms responsible for these effects of amino acids are largely unknown. The regulatory roles of amino acids in the immune system can be considered from two perspectives, namely, the enhancement of the immune response that protects individuals from infections and malignant neoplasms, and the reduction of over-responses such as inflammation and autoimmunity. In this review, we focus on the regulatory roles of amino acids in the immune response, showing how several amino acids (e.g., glutamine, arginine, tryptophan, cystine/cysteine, glutamate, and branched-chain amino acids) enhance immunity. Additionally, we describe how one amino acid, histidine, functions as an anti-inflammatory agent in colitis.

The use of complimentary and alternative medicine (CAM) approaches is becoming increasingly popular among patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Arthritis is a leading cause of work-related disabilities affecting approximately 1.0% of the United States population. The lack of adequate response combined with increased risk of adverse events to conventional therapy in RA or OA patients has prompted interest in evaluating CAM options for arthritis. In this regard, the last decade has shown a growing popularity of green tea (GT) in the management of arthritis. Researchers are studying GT and its constituents to provide scientific rationale for its benefit in arthritis. This review summarizes the disease pathogenesis and novel therapeutic targets for the treatment of arthritis. I also tried to address the current treatment options that are available as well as their limitations. Finally, this article reviews the emerging role of GT and its polyphenol, epigallocatechin-3-gallate (EGCG), in arthritis. Although the recent findings provide scientific evidence of the efficacy of GT or EGCG in several in vitro and in vivo models of arthritis, further preclinical studies to validate its safety profile and additional phase-clinical trials in RA patients are warranted to authenticate its beneficial effect in arthritis and possibly other rheumatic conditions.

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon found in cigarette smoke, grilled meats and byproducts of industrial incineration. BaP exposure through cigarette smoking has been implicated in the pathogenesis of lung and head-and-neck cancers and atherosclerosis. BaP inhalation activates the aryl hydrocarbon receptor (AHR), a transcription factor that induces expression of genes involved in xenobiotic metabolism. BaP can be metabolized to active compounds that form DNA adducts and induce the production of reactive oxygen species in cells, leading to inflammatory cytokine production. Polymorphisms of cytochrome P450 enzymes that are induced by AHR and function in BaP metabolism have been reported to confer increased risk of rheumatoid arthritis in Asian populations. AHR induces T cell differentiation to both immunoregulatory and autoimmune/inflammatory lineages. Dynamic metabolic activation of BaP and cell type-specific AHR activation may influence AHR-regulated immune responses. An improved understanding of AHR function should provide pharmacologic approaches to BaP detoxification useful in the prevention of diseases associated with environmental pollutants, such as rheumatoid arthritis.