Inflamation

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.

Arthritis - Rheumatoid
Natural Therapies for Rheumatoid Arthritis

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-a 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 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-a 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 called BCM-95®, 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 genus of the boswellia sacra tree contains a powerful anti-inflammatory compound called 3-acetyl-11-keto-ß-boswellic acid (AKBA). Boswellia serrata extract (BSE) contains high levels of these boswellic acids, which are potent inhibitors of 5-lipoxygenase (5-LOX), a pro-inflammatory enzyme. 5-LOX leads to the production of inflammatory producing leukotrienes. BSE may also have inhibitory effects on pro-inflammatory proteins like TNF-a (Ammon 2006). These acids have even been shown to have immunomodulatory effects similar to NSAIDs (Abdel-Tawab 2001). A study investigating the effect of consuming BSE standardized to 30% AKBA on arthritis found that this extract significantly improved joint flexion, reduced swelling, and protected the joint from cartilage degradation induced by inflammation (Sengupta 2011). An improved extract called AprèsFlex™ (a.k.a. Aflapin®), which combines AKBA with other non-volatile boswellia oils, demonstrated improved activity at a lower concentration when compared to other preparations standardized to the same percentage of AKBA (Sengupta 2010).

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). 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 controlled trial, 450 rheumatoid arthritis patients were treated for 12 weeks with either a daily dose of 1.8 g total glucosides of peony or a weekly dose of 10 mg methotrexate, an immunosuppressive anti-rheumatic medication (Gold Standard 2016). A therapeutic response was achieved in 71.7% of the peony-treated group. These results were later confirmed in a more advanced clinical trial in over 1000 patients 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, speeding symptom relief and reducing side effects (Chen, Li 2013; Du 2005; Wang 2007; Xiang 2015; Zhao 2006). Other clinical studies indicate 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 over-activation, total glucosides of peony strengthens immune regulation and quiets immune over-activity (He 2011). In animal models of rheumatoid arthritis, paeoniflorin alone has demonstrated similar immune-regulatory effects in immune cells (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).