What is Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes pain and disfigurement of peripheral joints. The disease may alternate between “flares” and periods of remission, but is generally progressive. Importantly, patients with RA are at a significantly higher risk of cardiovascular disease.

The disease is characterized by an autoimmune response that can damage joints and cause systemic inflammation. The inflammation is caused by the immune system mistakenly attacking the soft tissue in joints, causing damage and dysfunction.

Natural interventions like curcumin, Boswellia serrata extract, and white peony extract may help reduce inflammation and improve overall health in patients with RA.

What are the Signs and Symptoms of Rheumatoid Arthritis?

• Joint inflammation (swollen, warm, painful)—may be worse in the morning
• Fatigue
• Malaise
• Weight loss
• Damage to other areas of the body may occur as well. Some symptoms may include ulcers on the skin, coughing or shortness of breath, high cholesterol, and anemia.

What are the Conventional Medical Treatments for Rheumatoid Arthritis?

• Disease-modifying antirheumatic drugs (DMARDs) (eg, methotrexate and sulfasalazine)
• Glucocorticoids (eg, prednisone)
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Statins to prevent cardiovascular disease

What are Emerging Therapies for Rheumatoid Arthritis?

• Modified-release prednisone to improve on the action of conventional prednisone
• Stem cell treatment
• Bioidentical hormone replacement therapy

What Dietary and Lifestyle Changes Can Benefit Rheumatoid Arthritis?

• Avoid foods that cause sensitivities (elevated IgG antibodies)
• Exercise (dynamic aerobic exercise and/or strength training)

What Natural Interventions May Benefit Rheumatoid Arthritis?

• Undenatured type-II collagen. When immune cells encounter exposed joint collagen in RA patients, an autoimmune attack is launched, resulting in inflammation. Consuming undenatured type-II collagen may help the immune system develop “oral tolerance,” teaching the T cells to ignore collagen encountered in joints.
• Essential fatty acids. Omega-3 and certain omega-6 fatty acids are recommended for many RA patients because they can reduce inflammation and improve cardiovascular health. Fatty acids derived from fish oil have been shown to reduce RA pain and improve cholesterol and triglyceride levels.
• Vitamin D. Vitamin D plays an immunomodulatory role and can improve pain relief in RA patients taking DMARDs.
• Vitamin B6. Treatment with vitamin B6 reduced levels of pro-inflammatory cytokines in patients with RA. Patients with RA are also more likely to be deficient in vitamin B6.
• White peony extract. Multiple studies have shown that white peony extract has immunomodulatory, anti-inflammatory, and pain-relieving activity. The extract can reduce symptoms on its own and improve patient response to other treatments.
• Curcumin. Curcumin is a well-known anti-inflammatory compound. It has been shown to be as effective as an NSAID in treating RA-related activity.
• Boswellia serrata extract. The anti-inflammatory extract of the Boswellia sacra tree can improve joint flexion, reduce swelling, and prevent cartilage degradation in arthritic patients.
• Pomegranate. Pomegranates are rich in antioxidant polyphenols. Animal studies and small clinical trials have demonstrated pomegranate’s ability to help with arthritic pain and inflammation.
• Other plant extracts and compounds such as andrographis, green tea, ginger, and quercetin may help reduce inflammation as well.
• Supplemental forms of several endogenous compounds may be important for preventing inflammation and damage, including S-adenosyl-L-methionine (SAMe), glucosamine, and chondroitin sulfate.

Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by an autoimmune response that causes pain and disfigurement in peripheral joints. A dangerously underappreciated fact about RA is that it also significantly increases risk of cardiovascular disease. Because systemic inflammation hastens the onset of most age-related diseases, individuals afflicted with RA have a nearly 40% increased risk of dying compared to healthy people (Khan 2010; Radovits 2010; Peters 2009).

Too often, conventional treatment strategies yield only marginal relief and fall pitifully short of mitigating the systemic risks that threaten the longevity of RA patients. Life Extension encourages both patients and physicians to view RA as a disease of the entire body, not just the joints. Initiating an aggressive cardiovascular risk reduction program should be as high a priority as relieving joint pain.

In this protocol, you will discover an advanced European drug delivery system that dramatically augments the efficacy and lessens the side effects of prednisone, a drug commonly used in the treatment of RA. You will also learn about oral tolerance – a unique, drug-free strategy that helps re-train the immune system to not attack the joints, as well as convenient blood tests and scientifically studied natural compounds that allow you to assess and target your cardiovascular risk.

The prominent feature of rheumatoid arthritis is joint inflammation. Affected joints are usually swollen, warm, painful and stiff. These symptoms typically worsen in the morning but, at least early in the disease process, can sometimes be eased by gentle movement. As the disease progresses, however, these symptoms often increase in severity until movement is severely impaired.

Inflammation associated with RA is systemic, meaning that it is not isolated to only those joints affected. RA tends to present symptoms in a symmetrical way. For example, if the joints of the right hand are inflamed, the joints of the left hand are likely to be inflamed as well (St. Clair 2004). While the hand and wrist joints are most often affected, other joints may be involved including those of the feet and ankles, knees, hips, elbows, shoulders, and the cervical spine (i.e., the neck) (Klippel 2010).

In general, the symptoms and severity of RA follow one of three patterns (Ruffing 2012):

• Spontaneous remission: The symptoms ultimately disappear, which occurs in less than 10% of patients with RA. This generally occurs only in patients whose blood tests are negative for a protein called rheumatoid factor (RF), an autoimmune mediator.
• Relapsing/remitting disease: The patient experiences periods of very severe symptoms called "flares", which are contrasted with episodes of mild or no symptoms. This pattern generally occurs early on in the course of the disease.
• Persistent and progressive disease: Disease activity gets progressively worse. However, flares and periods of remission are not as dramatic as relapsing/remitting disease. This is the most common course of disease.

During the course of the disease process, RA mediated inflammation can cause permanent damage to several tissues in the body, especially the joints (NIAMS 2009).

In RA, the immune system mistakenly attacks healthy cells and tissues – predominantly the synovium, the soft tissue between the articular capsule (joint capsule) and the joint cavity of synovial joints. This immune mediated assault leads to the development of pannus, a destructive fibrous tissue within affected joints that erodes cartilage and exacerbates joint dysfunction.

RA damage is engendered by multiple components of the immune system, including antibodies and killer T-cells.

Antibodies are proteins secreted by B-cells that normally recognize and bind to invading microbes such as bacteria and viruses. By attaching to the invading microbe, they activate other components of the immune system to launch an inflammatory response, which destroys the cells.

In RA, antibodies mistakenly recognize "self" cells as invaders. Once antibodies attach to synovial cells in the joint, they attract a variety of immune cells that launch a devastating inflammatory attack. The complex inflammatory process within joints is mediated in large by the cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The inflammatory damage is not limited to the synovium, but spills over to the chondrocytes (cartilage cells that cushion joints). This process raises the level of dangerous inflammatory compounds throughout the body, including C-reactive protein (CRP), which is a marker of inflammation and can be evaluated via a high-sensitivity CRP (hs-CRP) test.

Another kind of immune system cell that develops in the thymus and contributes to RA is the T-cell. One T-cell sub-type—the "killer" T-cell—can directly kill other cells. This is useful in eradicating invading microbes, but in the case of RA, killer T-cells contribute to tissue damage by directly damaging joints and other affected organs.

An important pathological feature of arthritis is the exposure of collagen as a result of cartilage deterioration. When a joint is sufficiently damaged, collagen (a protein component of cartilage) becomes exposed to circulating immune cells, which attack it. This process promotes further inflammatory joint destruction.

Under normal circumstances, joint tissue can repair itself. However, joints may become permanently weakened and deformed if inflammation is severe, chronic, and occurs over many years as with RA.

Inflammatory Damage Associated with Rheumatoid Arthritis Extends Beyond the Joints.

Once the immune system is activated against self-tissue, it sends inflammatory chemicals through the body resulting in widespread damage. For many patients it causes fatigue, malaise and unexplained weight loss.

Other areas targeted by the immune system in RA can include the skin, lungs, eyes, blood, nervous system, heart, and bones. Signs and symptoms may include (Klippel 2010; St. Clair 2004; Cush 2005):

• Skin: Nodules and ulcers on the surface of the skin occur in 50% of people with RA (Mikuls 2007).
• Lungs: RA may cause interstitial lung disease, resulting in a dry cough and shortness of breath that may worsen with physical activity; 20-30% of people with RA have some form of lung disease (Kahlenberg 2011).
• Eyes: Inflamed eyes are common and affect up to 25% of people with RA. Parts of the eye often targeted include the cornea, conjunctiva, and sclera (the white portion of the eye).
• Blood: Anemia and low iron levels often occur in RA and can cause fatigue, fast heartbeat, dizziness and pale skin.
• Nervous system: Degeneration of the cervical vertebrae of the spine can compress the spinal cord in the neck area, causing pain on top of that caused by synovitis (inflammation of the synovium).
• Heart: People with RA are at a two-fold greater risk of developing heart disease, thus contributing to the 40% greater mortality rate of people with RA compared to the general population (Radovits 2010; Peters 2009). Even early in the disease process, RA patients are prone to endothelial dysfunction due to increased circulating inflammatory molecules. Endothelial cells are the delicate cells lining the inside of blood vessels. Endothelial dysfunction is the initial stage of potentially fatal atherosclerotic vascular disease (Tanasescu 2009).
• Bones: People with RA have a significantly increased risk of bone fractures. Both the disease and medicine(s) used to treat RA (e.g., corticosteroids) can cause bone loss, which increases the risk of bone fractures (Spector 1993).
• Dyslipidemia: People who have RA are more likely to have dyslipidemia (elevated levels of cholesterol and triglycerides in blood) (Park 1999; Boers 2003). One study showed dyslipidemia 10 years before the development of RA (van Halm 2007). Therefore, it is important that people with both dyslipidemia and a family history of RA focus on prevention and monitor their health very closely. Dyslipidemia and endothelial dysfunction synergize to dramatically compromise the cardiovascular health of RA patients.

The two important factors to consider when diagnosing RA are 1) whether inflammation is present, and 2) whether an autoimmune response is occurring. Inflammation can be measured with a variety of blood tests including hs-CRP (measures inflammation quantitatively) and an erythrocyte sedimentation rate (ESR) test (measures inflammation functionally) (St. Clair 2004).

To help determine if an autoimmune reaction is taking place, doctors often assess the levels of two proteins: rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA), sometimes referred to as anti-cyclic citrullinated protein (anti-CCP). Both RF and ACPA are autoantibodies involved in the immune attack against self-tissue in RA.

Table 1. Criteria for a definitive diagnosis of rheumatoid arthritis.> A definitive diagnosis requires confirming synovitis due to RA in at least one joint. Additionally, a total score ≥ 6 by adding the individual criterion scores below (Aletaha 2010; Pietschmann 2011).

Rheumatoid Arthritis patients display a greater propensity for food allergies and sensitivities, a link that evidence indicates may be more than coincidental (Hvatum 2006). In fact, studies suggest that reactions originating in the gut may fuel systemic inflammatory fires, thereby exacerbating RA symptoms. Support for this theory appeared in the peer-reviewed literature as early as the late 1940's (Zeller 1949).

Immunologic reactions to components of certain foods in many ways resemble the self-reactivity seen in RA and other autoimmune diseases; that is, the immune system mistakenly attacks non-pathogenic molecules. Therefore, it may be possible to calm the immune system by eliminating unnecessary molecular triggers found in certain foods. Studies have shown that RA patients produce significantly more intestinal antibodies against various foods than healthy controls (Hvatum 2006). In a 12-week clinical trial, adherence to an allergen-restricted or allergen-free diet corresponded with symptomatic improvement for a small number of subjects (van de Laar 1992). When allergens were reintroduced into their diets, symptoms reemerged. Vegetarian, vegan, and gluten-free diets have been linked to symptomatic relief in RA patients (Muller 2001; Hafstrom 2001). Interestingly, a recent review of genome-wide association studies revealed that people with celiac disease (characterized by gluten sensitivity) and those with RA shared genetic similarities (Zhernakova 2011).

Based on the connection between food and rheumatism, avoiding foods that result in elevated IgG antibodies in the blood may be an underappreciated method of relieving RA symptoms. Low-cost IgG blood testing allows RA patients to pinpoint potentially problematic foods and begin eating a diet that best suits their immunological profile.

Oral Tolerance and Undenatured Type-II Collagen

Immune system T-cells are tasked with recognizing and distinguishing between "self" and "foreign" molecules. They do this by responding to very specific molecular shapes and 3-dimensional structures (Bagchi 2002). If T-cells in the blood are simply exposed without any "training" to a previously unrecognized protein structure (such as those found in joint collagen), they react violently and trigger a massive inflammatory response to destroy the protein (Cremer 1998).

When scientists want to create an animal model of arthritis they inject collagen into their subjects, thereby sensitizing the T-cells in their blood to the collagen protein (Corthay 1998). Those circulating T-cells initiate inflammation in the animal's joints, which are rich in collagen.

With adequate preparation, T-cells can be "trained" to differentiate between friend and foe. One place this training happens is in the intestinal tract; specifically, the lower end of the small intestine, which is rich in collections of immune tissue called Peyer's patches. Peyer's patches contain T-cells, which become exposed to all sorts of molecular shapes that are natural components of the food we eat (Meyer 2000). In that fashion, we desensitize our immune systems and develop a natural tolerance to new foods without having constant allergic or inflammatory reactions.

By providing the correct 3-dimensional collagen to the digestive tract, we can "educate" our T-cells to ignore collagen when they encounter it in joints (Park 2009; Bagchi 2002). This phenomenon is dubbed oral tolerance to collagen.

Upon induction, oral tolerance to collagen suppresses joint inflammation, as has been demonstrated in numerous laboratory studies (Park 2009; Zhu 2007; Nagler-Anderson 1986). Oral administration of soluble type II collagen has even prevented experimentally induced arthritis by way of collagen injections (Min 2006; Nagler-Anderson 1986).

But not just any collagen will do. Typical commercial processing causes collagen to become denatured, uncoiling from its normal helical shape and losing its functional 3-dimensional structure. Denatured collagen has no beneficial effects on joint inflammation (Nagler-Anderson 1986).

A more natural form of collagen called undenatured type II collagen (UC-II®) has recently been developed (Zhao 2011). UC-II® retains its original 3-dimensional molecular structure, keeping it recognizable by T-cells in Peyer's patches. UC-II® is robust enough to survive the harsh conditions in the stomach and small intestine, arriving at Peyer's patches with its molecular structure intact (Bagchi 2002).

As mentioned previously, collagen exposure subsequent to joint deterioration is a key mechanism by which the immune system is driven to destroy joint tissue in arthritis. Therefore, retraining the immune system through induction of oral tolerance may be an effective means of easing the inflammatory rheumatic process.

The role of steroid hormones in autoimmunity is evidenced by differences between men and women in both immune function and incidence of autoimmune disease. For example, estrogen actions tend to be pro-inflammatory, while progesterone, androgens, and glucocorticoids are anti-inflammatory (Cutolo 2004). Studies have documented low progesterone levels in women with autoimmune diseases, suggesting that a relative imbalance in favor of estrogen may contribute to immune reactivity in some female patients (Shabanova 2008). In RA and other autoimmune diseases, estrogen levels appear to be driven too high by actions of inflammatory mediators like TNF-α and IL-6 (Cutolo 2006). In some studies, lower levels of testosterone have been observed in male patients with RA than in controls (Masi, 2006). Testosterone and progesterone functions to promote immune tolerance in males and females, respectively (Cutolo 2006). Therefore, ensuring adequate levels of progesterone to balance excess estrogen in women and sufficient levels of testosterone in men may modulate some underlying immunologic features of RA (Karlson 2009; Cutolo 2009). Medications used to treat RA symptoms have been shown to suppress sex hormone production as well, potentially compounding an existing hormone insufficiency or imbalance (Weitoft 2008).

While large-scale clinical trials have yet to evaluate the efficacy of bioidentical hormone replacement therapy in RA patients, Life Extension suggests that the potential for considerable benefit outweighs the minimal risk. Taking measures to achieve and maintain optimal levels of sex hormones may soon emerge as an effective strategy for the symptomatic management of RA. Those interested in reading more about natural bioidentical hormone replacement therapy should review the Male or Female Hormone Restoration protocols.

The role and therapeutic potential of the hormone dehydroepiandrosterone (DHEA) in male and female RA patients is supported by a broad base of evidence. Between ages 25 and 75, levels of the multifunctional hormone DHEA decrease by approximately 80% (Weiss 2011). Moreover, glucocorticoid therapy often employed in RA suppresses DHEA levels significantly (Yukioka 2006). The implications of low levels of DHEA may be considerable in RA, especially since DHEA counteracts the inflammatory cytokines TNF-α and IL-6 in the synovium. Conversely, local TNF-α suppresses DHEA levels in the synovium; thus, the relationship between the anti-inflammatory effects of DHEA and the pro-inflammatory effects of TNF-α are reciprocal in nature. In a one year, double-blinded, placebo controlled trial, 125 men and women aged 65 – 75 received 50 mg of DHEA daily. Treatment resulted in improved insulin sensitivity and lower levels of TNF-α and IL-6 in blood samples (Weiss 2011). These results were maintained during an additional year of open-label continuation.

Fatty Acids

Polyunsaturated fatty acids (PUFAs), primarily those derived from marine sources, have been recommended for RA patients for many years because of their ability to reduce inflammation and bolster cardiovascular health while helping soothe the overactive immune system (Goldberg 2007).

There are two main types of dietary PUFAs: omega-6 and omega-3. Both are important for health. However, it is especially important to maintain the correct ratio of omega-6 to omega-3 in the diet. Research has shown that the typical American diet is composed of an omega-6 to omega-3 ratio as high as 25:1 (Simopoulos 2011). The ideal ratio, however, is about 4:1, meaning very few people are getting enough omega-3 fatty acid relative to the amount of omega-6 (Holub 2002). A ratio so skewed toward omega-6 has the potential to be highly pro-inflammatory. Thus, it is essential for arthritis patients to get sufficient omega-3 fatty acids.

A number of trials have supported the benefit of RA patients consuming omega-3 fatty acids in the form of fish oil. These studies have shown that fish oil can help reduce the inflammation (Dawczynski 2011), pain and symptoms associated with RA. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), typically derived from fish oil, have proven anti-inflammatory properties. The results of a study in which people with RA consumed 1,800 mg EPA and 900 mg DHA daily for three months indicated that these fatty acids are effective in controlling morning stiffness, whereas those who received the placebo experienced worsening symptoms (Kremer 1985).

Numerous clinical studies have supported the benefits of RA patients consuming fish oil (James 1997). In a study assessing joint tenderness and dose of NSAIDs required to control symptoms in people with well-established RA, those consuming fish oil experienced less joint pain and took lower doses of NSAIDs (James 2010). Data from a separate study indicated that consuming fish oil may complement the anti-inflammatory properties of acetaminophen (Caughey 2010). Consuming fish oil also significantly reduced TNF-α and other pro-inflammatory cytokines (Endres 1989). Fish oil significantly improved cholesterol and triglyceride levels in people with RA as well, mitigating cardiovascular risk (Olendzki 2011).

Krill oil is a marine oil whose properties differ slightly from those of fish oil. In an animal model, krill oil "significantly reduced arthritis scores and swelling" (Ierna 2010). In a separate study of krill oil combined with hyaluronic acid and astaxanthin—both of which target pro-inflammatory agents in the body—arthritis patients reported a 55% pain reduction in under three months; 63% of participants were entirely pain-free post-treatment (Valensa 2011).

Gamma-linolenic acid (GLA): GLA is a beneficial omega-6 fatty acid found in oils from several different plants. Its heart healthy effects are well documented. In a study in which RA patients consumed 1400 mg GLA daily, their RA symptoms were significantly reduced, including number and severity of tender joints and degree of swelling (Leventhal 1993). A thorough review of clinical trials found that whereas consuming 1,400 mg daily or more of GLA resulted in a significant improvement in RA related symptoms, lower doses (i.e., 500 mg daily) did not appear effective (Cameron 2009). Other studies have shown that the following GLA-rich oils may be beneficial in people with RA:

Blackcurrant seed oil (Ribes nigrum): A 24-week clinical trial involving people with RA compared the effects of blackcurrant oil to placebo and found that blackcurrant seed oil significantly improved RA related symptoms (Leventhal 1994).

Borage seed oil (Borago officinalis): Oil from the borage plant seed is rich in GLA. Borage seed oil was used as the source of GLA in the study testing the benefits of GLA in reducing RA symptoms (Leventhal 1993). Results from a comprehensive review indicate that borage seed oil is associated with improved clinical outcomes in people with RA (Macfarlane 2011).

A recent clinical study found that RA patients consuming borage seed oil had decreased levels of total cholesterol, LDL, triglycerides, and increased HDL levels (Olendski 2011). This effect is particularly beneficial for people with RA as they have a greater risk of heart disease than the general population (Radovits 2010; Peters 2009).

Evening primrose oil (Oenothera biennis): A review showed that primrose oil effectively reduced RA symptoms (Cameron 2011). In one study, people with RA taking daily NSAID therapy consumed either 6 g per day of evening primrose oil or placebo. Those receiving daily doses of evening primrose oil experienced less morning stiffness after 3 months and less pain after 6 months (Brzeski 1991).

Vitamins

Vitamin K: Vitamin K, an antioxidant and anti-inflammatory agent that plays a role in bone metabolism and blood coagulation, is actually a group of closely related compounds that includes vitamin K1 (phylloquinone) and vitamin K2 (menaquinone). Vitamin K1 is more abundantly found in foods but is less bioactive than vitamin K2, which has a number of different subtypes. Menaquinone-4 (MK-4) and menaquinone-7 (MK-7) are the most important forms of vitamin K2. Menaquinones are mainly found in animal organs, such as the liver, or in bacterially fermented foods, such as soy, yogurt, and cheese (Grober 2014).

Animal research indicates oral supplementation with vitamin K plays a role in the expression of genes involved in the inflammatory pathways (Ohsaki 2006). A one-year study in over 500 elderly individuals found that dietary phylloquinone intake was associated with an improvement in markers related to insulin resistance and chronic inflammatory diseases (Juanola-Falgarona 2013). Cellular and animal research indicates that MK-4 inhibited the proliferation of rheumatoid synovial cells and inhibited collagen-induced arthritis in rats (Okamoto 2007).

In a cross-sectional study of 158 female RA patients not on warfarin or teriparatide, 70 individuals were treated with 45 mg/day of vitamin K2. The treatment group exhibited lower levels of inflammatory markers, including CRP, compared with the group that received no treatment. In addition, a longitudinal component of this study examined 52 patients who took vitamin K along with their medications for three months. These patients showed statistically significant decreases in serum CRP (Ebina 2013).

In a randomized controlled trial of 84 subjects being treated for RA, the group receiving 100 µg/day of MK-7 had reduced inflammatory markers compared with the control group. MK-7 has a longer half-life and is more bioavailable than MK-4 (Rheaume-Bleue 2015). Vitamin K vitamers have the potential to combat inflammation and improve joint health, although further research is warranted.

Vitamin D, which is synthesized when the skin comes into contact with ultra-violet light, plays an important immunomodulatory role and appears to appreciably ease RA symptoms. The results of a randomized clinical trial showed that RA patients taking a low dose of 1-25 dihydroxyvitamin D along with their disease modifying antirheumatic drug (DMARD) therapy had significantly greater pain relief at 3 months compared with the group receiving DMARDs only (Gopinath 2011). Alarmingly, a recent Swiss trial found that 86% of 272 RA patients had deficient or insufficient levels of vitamin D (Stoll 2011).

The vitamin D receptor (VDR), which binds vitamin D is located on the surface of immune cells. Because immune cells play an important role in promoting inflammation in RA, it seems logical that vitamin D would also have a role in RA mediated inflammation. Indeed, a recent study found that the VDR is important in limiting the inflammatory tendency of immune cells in a mouse model of RA (Zwerina 2011).

However, vitamin D does more than just arrest damaging immune cells; it also supercharges protective immune cells.

T-reg cells are specialized components of the immune system that help keep immunity balanced. If too few T-reg cells are present, the immune system becomes overactive as in autoimmune diseases like RA. Vitamin D increases the number of protective T-reg cells, restoring equilibrium to an overactive immune system (Cooney 2011).

Vitamin B6: The prevalence of vitamin B6 deficiency is elevated in people with RA. This deficiency has been associated with more severe symptoms (Chiang 2003). A study found that treatment with 100mg daily of vitamin B6 reduced blood levels of TNF-α and other pro-inflammatory cytokines in people with RA (Huang 2010).

Folate: A folate deficiency is particularly common in people RA being treated with methotrexate, as this drug depletes folate (Whittle 2004). Therefore, folate supplementation may be beneficial for people with RA.

Plants and Plant-derived Compounds

Andrographis: Andrographolides, components extracted from the plant Andrographis paniculata, inhibit activity of the pro-inflammatory compound known as inducible nitric oxide synthase (iNOS). This helps exert a powerful anti-inflammatory effect (Chiou 2000). Readers who are familiar with the vascular benefits of eNOS (endothelial NOS) should note that unlike eNOS, iNOS is pro-inflammatory and often involved in disease states where it is desirable to inhibit its actions.

Andrographolides suppress production of the pro-inflammatory cytokines TNF-alpha and prostaglandin E2 (PGE-2), preventing their gene expression at multiple levels (Liu 2007(a,b)). By doing so they downregulate the chemical signaling pathways that cells use to "tell" each other to initiate the inflammatory response, which plays a key role in rheumatoid arthritis (Liu 2008).

Scientific analysis has further revealed that andrographolides operate "upstream" within the process of the inflammatory cascade by blocking the effects of the pro-inflammatory transcription factor nuclear factor-kappaB (NF-kB) (Bao 2009).

NF-kB is found in almost all human cells. It plays a key role in cellular responses to stress, cytokines, free radicals, oxidized low-density lipoprotein (LDL), and bacterial or viral pathogens. Accordingly, its central role as a first-responder to oxidative damage, infection, and toxin-induced stress links it to inflammation, cancer, and chronic disease (Ahn 2005). NF-kB tightly regulates virtually all factors that are downstream in the inflammatory cascade, including cytokines known as interleukins, hormones known as prostaglandins, and TNF-alpha.

By blocking NF-kB, andrographolides inhibit production of a host of inflammatory mediators in one simple step (Chao 2009). As demonstrated in animal studies, they also permit normal activity of vital immune surveillance cells as they simultaneously suppress over-active inflammatory cells (Naik 2009).

This is a critical feature that distinguishes andrographolides from most anti-rheumatic drugs (DMARDS). Whereas andrographolides suppress inflammatory immune factors, DMARDs can suppress immune function in general resulting in an increased risk of infection (Manganelli 1993).

Curcumin: Curcumin is an antioxidant compound found in the spice turmeric and has potent anti-inflammatory and immunomodulatory properties. One laboratory based study showed that curcumin reduces synovial inflammation (Jackson 2006). Specifically, this study demonstrated that exposing inflamed synovial cells to curcumin not only reduced the inflammatory state of these cells, but suppressed the production of pro-inflammatory proteins and the activation of cells with inflammatory properties.

Curcumin also helps protect cartilage from inflammation mediated destruction. A meta-analysis sought to examine the body of evidence concerning the effect of curcumin on chondrocytes, the cells that make up cartilage. The researchers concluded that curcumin not only helps prevent the degradation of cartilage induced by certain inflammatory proteins in the joint (Henrotin 2010), but it also helps promote cartilage regeneration (Buhrmann 2010).

Curcumin may also help lower the dose of methotrexate required for therapeutic effects and drug-related liver toxicity. One study found that administering curcumin along with a very low, sub-therapeutic dose of methotrexate in a mouse model of arthritis effectively treated the inflammation while reducing the level of drug-induced liver damage (Banji 2011). If as effective in humans, taking curcumin along with methotrexate would enable people with RA to take lower doses of methotrexate, thereby decreasing their risk of liver toxicity.

One small (18 people) but well-designed study found that consuming curcumin resulted in improved ambulation (increase in time) as well as a significant reduction in joint swelling and morning stiffness (Deodhar 1980). These results were corroborated by a larger clinical trial in which 45 RA patients were randomized to receive 50 mg of diclofenac sodium, 500 mg of a highly absorbable form of curcumin, or both for 8 weeks. In this trial, curcumin alone and in combination with diclofenac sodium proved to be at least as effective as diclofenac sodium alone in easing RA disease activity, as measured by multiple standardized assessments. In addition, curcumin alone powerfully suppressed CRP (a marker of inflammation in the blood) by 52% from baseline, while diclofenac sodium alone only decreased CRP by 1.5%. The investigators of this trial remarked that "Taken together, our present results provide a clear proof-of-principle for the superiority of curcumin, and the lack of any synergistic or additive efficacy when used in conjunction with diclofenac strongly favours the safe and effective application of curcumin alone in clinical settings for the management of rheumatoid arthritis, and other proinflammatory diseases including cancer in the future" (Chandran 2012).

Quercetin: Quercetin is a flavonoid compound rich in fruits and vegetables -- especially apples, citrus fruits, parsley, sage and onions. Quercetin strongly inhibits multiple components of the inflammatory process, including the COX enzymes that are targeted by NSAIDs (Lee 2010). Laboratory experiments with synovial cells have shown that although quercetin does not have an effect on the production of pro-inflammatory proteins, it directly reduces inflammation in the synovium as well as the activation of pro-inflammatory cells (Jackson 2006).

A recent proof-of-concept study demonstrated decreased inflammation by utilizing bioengineering techniques to increase the bioavailability of quercetin in a rat model of RA. The investigators loaded quercetin into microspheres and delivered the microsphere-quercetin combination directly into the joint (Natarajan 2011). The microspheres enabled the quercetin to be released consistently over 30 days. Although additional human trials are needed, the data thus far supports an anti-inflammatory role for quercetin in RA.

Boswellia serrata extract: Resin from the Boswellia serrata plant contains an anti-inflammatory compound called 3-acetyl-11-keto-β-boswellic acid (AKBA). Boswellia serrata extract also contains high levels of boswellic acids, which are potent inhibitors of 5-lipoxygenase (5-LOX), an enzyme that produces inflammatory leukotrienes. Boswellia serrata extract may also have inhibitory effects on pro-inflammatory proteins such as TNF-α (Ammon 2006). Extracts of Boswellia have been shown to improve arthritic symptoms and reduce inflammatory activity and markers in animal models of rheumatoid arthritis (Banji 2022; Kumar 2019). And Boswellia has historically been used in Ayurvedic medicine for inflammatory, painful conditions like rheumatoid arthritis (Sethi 2022).

One placebo-controlled clinical study in 260 participants with rheumatoid arthritis found that Boswellia extract effectively improved symptoms like joint swelling, pain, and stiffness; it also improved erythrocyte sedimentation rate, suggesting an improvement in inflammation (Etzel 1996). Another placebo-controlled study in 182 patients with rheumatoid arthritis found that 16 weeks of treatment with a combination of Ayurvedic plant extracts (including Boswellia) led to improvement in joint swelling compared with placebo (Chopra 2000).

Pomegranate: Pomegranates contain a high concentration of polyphenols, which are compounds with strong antioxidant properties. Pomegranate seeds are either eaten in their natural form or processed to produce pomegranate juice. Alternatively, the active compounds can be extracted from the rest of the fruit's components.

One study tested the severity of inflammation and incidence of arthritis in mice fed a pomegranate extract in addition to their food. The mice in the pomegranate fed group had a lower incidence of arthritis, and those who did get arthritis developed it later than normal (i.e., delayed disease) as well as having reduced joint inflammation and damage (Shukla 2008).

In a recent pilot study testing the efficacy of pomegranate extract in 6 people with RA, it was reported that the people consuming the extract had significantly fewer tender joints (Balbir-Gurman 2011). Expanding the sample size of patients studied will determine if these effects are broadly applicable.

Green tea: The active ingredient in green tea is epigallocatechin 3-gallate (EGCG), which has been tested extensively for its health promoting properties. EGCG has been shown to have significant anti-inflammatory and antioxidant effects as well as helping to optimize the lipid profile (Ahmed 2010).

Pre-clinical studies indicate that green tea may be effective in reducing inflammation in the joints of people with RA. For example, supplementing drinking water with green tea significantly reduced the severity of arthritis in a rat model of RA (Kim 2008). It was even effective in preventing the onset of arthritis in a mouse model of RA (Haqqi 1999).

Ginger: Ginger, the underground stem of the Zingiber officinale plant, has potent anti-inflammatory and antioxidant properties (Grzanna 2005). Ginger directly suppresses inflammation by inhibiting pro-inflammatory enzymes and blocking the production of pro-inflammatory proteins (Nievergelt 2011). Furthermore, several investigators have reported that consuming ginger significantly prevented the onset of arthritis in rodent models of RA (Funk 2009; Ramadan 2011; Fouda 2009).

Nigella sativa seeds: These seeds are commonly called "black cumin" or "black caraway." Investigators have shown that consuming thymoquinone, the active compound of the seed oil, inhibited inflammation and prevented arthritis in a rat model of RA (Tekeoglu 2007).

A recent study compared the symptoms of RA patients receiving 500 mg of Nigella sativa oil twice daily for one month with those receiving placebo capsules. Remarkably, up to 40% (which varied approximately 10% based upon the disease activity scale used to assess symptoms) of people receiving Nigella sativa seed oil experienced an improvement in RA symptoms (Gheita 2011).

Beta-sitosterol and beta-sistosterol glucoside: As suggested by some preliminary research, a proprietary 99:1 mixture of beta-sistosterol (BSS) and beta-sitosterol glucoside (BSSG) called Moducare® may modulate immunity in RA. In laboratory experiments a BSS/BSSG blend has demonstrated an ability to balance immune cell function under varying conditions (Ju 2004; Anonymous 2001). Two small pilot studies in human subjects have corroborated the in vitro data. In the first study, 17 ultra-marathon runners were given either the BSS/BSSG mixture or a placebo. After the race, when immune function is normally drastically altered, researchers assessed parameters of inflammation in both groups. In the group taking the BSS/BSSG mixture, it was noted that levels of immune cells rose while inflammatory mediators in the blood declined, suggesting that the mixture primed the immune system for defense while simultaneously suppressing excess inflammation (Bouic 1999). In the second trial, 18 patients with active RA took the either the BSS/BSSG mixture or placebo for 24 weeks. The mixture lead to significant improvements compared to placebo in all of the following: measurable tender joint count, patient's assessment of pain, patient's global assessment of disease activity, and physician's global assessment of pain. Furthermore, erythrocyte sedimentation rate (ESR), an assessment of the inflammatory tendency of blood, decreased by 56% (Louw 2002).

White peony extract: White peony (Paeonia lactiflora) root is a traditional Chinese medicinal herb that contains bioactive compounds called glucosides. A water and alcohol extract of the peony root, known as total glucosides of peony, has more than 15 identified compounds. The most active and abundant of these is paeoniflorin, which represents more than 90% of the total glucosides of peony (Feng 2016; He 2011). A number of studies have shown paeoniflorin and total glucosides of peony have immunomodulatory, anti-inflammatory, and pain-relieving properties, and provide support for peony’s historical use in the treatment of autoimmune conditions in general and rheumatoid arthritis in particular (Feng 2016; Zhang 2012; Lindler 2020). In 1998, the State Food and Drug Administration of China approved total glucosides of peony for the treatment of rheumatoid arthritis (He 2011).

In a meta-analysis of eight randomized controlled trials involving 522 participants with rheumatoid arthritis, total glucosides of peony combined with methotrexate had better therapeutic efficacy than methotrexate alone, including a greater decrease in ESR and swollen joint count. Additionally, fewer adverse events were reported in the combination group than methotrexate alone (Feng 2018).

In a controlled trial, 450 people with rheumatoid arthritis were treated for 12 weeks with either 1.8 grams of total glucosides of peony daily or 10 mg of methotrexate weekly, an immunosuppressive anti-rheumatic medication (Gold Standard 2016). A therapeutic response was achieved in about 72% of the peony-treated group. These results were later confirmed in a more advanced clinical trial in over 1,000 people with rheumatoid arthritis (He 2011). Several clinical trials have studied the effect of total glucosides of peony in combination with methotrexate or leflunomide, another anti-rheumatic medication, and found that peony extract can protect against the liver toxicity of methotrexate and improve response to treatment compared with the medications alone (Chen, Li 2013; Du 2005; Wang 2007; Xiang 2015; Zhao 2006; Liu 2021).

Other clinical studies have found that total glucosides of peony may also be helpful in other types of autoimmune arthritis, including juvenile idiopathic arthritis and psoriatic arthritis (Cai 2016; Wang 2014).

Studies using animal models of inflammatory arthritis also demonstrated the anti-inflammatory and anti-rheumatic potential of total glucosides of peony (Zheng 2007; Liu 2010; Lin 2012; Jia 2014). In one study, treatment with total glucosides of peony inhibited inflammatory cytokine production by joint cells and prevented bone destruction around affected joints (Wei 2013).

Laboratory and animal investigations into the actions of total glucosides of peony indicate that in conditions of immune overactivation, total glucosides of peony modulates immunological system activity (He 2011). In animal models of rheumatoid arthritis, paeoniflorin alone has demonstrated similar immune-modulating effects (Zhang 2015; Zhai 2016; Chen, Guo 2013).

Endogenous Compounds

SAMe: S-adenosyl-L-methionine (SAMe) is a natural compound in the body that is necessary for many different physiological processes. SAMe has been shown to improve symptoms of osteoarthritis, liver disease, and even depression. Although most scientific research has focused on osteoarthritis, the mechanisms for SAMe suggest a role in RA. SAMe supports the production of the structural components of cartilage, which can be destroyed by the chronic inflammation of RA. The anti-inflammatory properties of SAMe suggest a supportive role for this compound in RA patients (Talbott 2007).

A comprehensive review of several individual clinical studies found that SAMe relieved pain and improved joint function in people with osteoarthritis (Rutjes 2009). In fact, SAMe had similar analgesic and function improving effects as treatment with NSAIDs, but without the adverse effects (Soeken 2002).

The common RA medicine methotrexate has been shown to inhibit cell signaling through the SAMe pathway (Nesher 1996). Therefore, the cells in joint tissue may not process SAMe normally. This laboratory study suggests that people treated with methotrexate may benefit from SAMe supplementation.

Glucosamine: This compound is a precursor to glycosaminoglycans, components of larger molecules – proteoglycans – which are incorporated into cartilage. Proteoglycans are critical for healthy cartilage and proper cushioning of the joint because they draw water into the joint, acting as a lubricant. In addition, glucosamine seems to have some anti-inflammatory properties (Talbott 2007).

Glucosamine has been shown to suppress production of the pro-inflammatory cytokine IL-8 in cells of the synovium (Hua 207). Another study found that glucosamine was effective in significantly reducing RA symptoms despite no detectable differences in conventional markers of inflammation such as CRP (Nakamura 2007).

Chondroitin sulfate: This compound is a structural component of cartilage. When taken as a supplement, it helps fight inflammation and supports the rebuilding of cartilage (Talbott 2007). Chondroitin sulfate may be healthy for the heart as well. An animal model of atherosclerosis and chronic arthritis found that chondroitin sulfate prevented atherosclerotic lesions from developing (Martinez-Calatrava 2010). This data, although very preliminary, raises the possibility that chondroitin sulfate may help fight the systemic inflammation present in RA that leads to joint and heart disease.

Exercise

As with other rheumatic diseases, exercise is a critical component of maintaining muscle mass, supporting a healthy heart, and preventing joint damage as much as possible. Various types of exercises are beneficial for people with RA.

Aerobic exercise: Several studies have demonstrated that dynamic aerobic exercises such as swimming, walking, and bike riding not only improve overall health and quality of life in patients with RA but also reduce pain. Another benefit of dynamic exercise is the improvement in cardiovascular health, which is especially important for people with RA (Cooney 2011). To date, no studies have reported that dynamic exercise has deleterious effects on disease activity or joint function (Van den Ende 1998; Cairns 2009). Even high-intensity exercise has not been shown to lead to increased inflammation or joint damage (Plasqui 2008).

Strength training: Strength training (e.g., weight lifting) involves applying resistance to various muscle groups to improve muscle strength. Similar to dynamic exercise, strength training reduced pain and improved function in people with RA (Flint-Wagner 2009).