Back to Table of ContentsGet A Grip On Arthritis
and other inflammatory disorders
Natural Remedies to Stop Inflammation
Many nutrients halt the action of inflammatory cytokines and prostaglandins without the side effects associated with drugs. They should be considered as excellent anti-inflammatory agents, including boswellia extracts, Celadrin, curcumin, fish oil and vitamins. General descriptions are included below in alphabetical order; specific recommendations for inflammatory conditions are included in the next section, under "Prescription for Health," in order of importance.
Boswellia, an extract from the Boswellia serrata tree, has been extensively studied in humans and found to have several power-ful anti-inflammatory effects. It inhibits inflammatory factors and the Cox enzyme pathway and therefore reduces inflammatory prostaglandins. It also acts as an analgesic and may improve circulation to damaged joints and inflamed tissue. In one study, 70 percent of rheumatoid arthritis patients had a reduction in pain and stiffness. To verify this finding, researchers gave 17 of the treatment patients receiving Boswellia the placebo pill instead, and their symptoms returned.
One of the newest, most effective, natural anti-inflammatory products is Celadrin, a patented blend of special fatty acids. Celadrin is available in capsules, tablets, soft gels or as a cream. Both humans and animals have shown remarkable improvements in terms of reduced pain and swelling, increased range of movement and reduction of inflammatory factors when using Celadrin.
Results of a double-blind, multi-center, placebo-controlled trial (the most scientifically validated type) published in the prestigious Journal of Rheumatology found that Celadrin, when taken orally, improved joint and mobility problems. Sixty-four participants between the ages of 37 and 77 were given Celadrin capsules. They were evaluated at the beginning, at 30 days and at the end of the 68-day study. Compared to those given a placebo, participants taking Celadrin had more flexibility, fewer aches, less pain and were able to walk longer distances than the placebo group.
On the anecdotal side, Tony Gwynn, eight-time National League batting title winner, has relied on Celadrin to undo 20 years of baseball damage to his knees, and Danny Milsap, an 84-year-old softball pitching legend, uses Celadrin to keep him in the game. In addition, Derek Boosey, Senior Olympic gold medalist in the triple jump in the 55 to 60 age class, has used oral and topical Celadrin to eliminate knee pain. He has also seen his levels of bad cholesterol fall, while his good cholesterol levels have risen; his CRP level is 0.13 mg/dL.
Celadrin is also currently being researched for the treatment of gingivitis, another common inflammatory disorder. Results are expected in 2005.
Research on the effectiveness of Celadrin cream performed at the University of Connecticut involved 42 patients with osteoarthritis of the knee. Participants received either Celadrin or a placebo cream applied topically. They were evaluated before application of the cream, 30 minutes after, and then again following a 30-day treatment period during which the cream was applied twice a day, morning and evening. The researchers evaluated physical function, postural sway, pain and range of motion. Test of physical function included a timed assessment of how long it took to get up and go from a chair, stair climbing, muscle strength and endurance, and mobility of the knee. The group receiving Celadrin had outstanding results with reduced pain and stiffness, improved balance and strength and better mobility. What was most exciting was that within 30 minutes of applying Celadrin cream, patients experienced a dramatic improvement in all aspects tested. (No difference in the ability to extend the leg was noted between groups.) Results of this study were published in The Journal of Rheumatology, August 2002. Another study using Celadrin Cream, performed as an extension of the previous study, confirmed earlier research showing improvement in elbow, wrist and knee mobility and significant reduction in pain.
Those using the oral form of Celadrin and the cream together experienced a much faster improvement in pain, swelling and mobility than those using the cream alone.
Celadrin Cream and Psoriasis: Another double-blind, placebo-controlled study using Celadrin cream for the treatment of psoriasis was performed over a 14-day period. Patients were asked to apply the cream to the affected area twice a day. Initial severity of skin scales, patchiness, redness, dryness, crack and raised skin was recorded. Then, after 7 and 14 days, each patient visited a dermatologist for evaluation of skin improvement. Each patient experienced a two-level improvement based on the 6-point Liker scale (0 = no improvement, 5 = significant improvement). This small pilot study found that those using Celadrin cream experienced measurable improvement in their psoriatic condition. Reports from those using Celadrin have sparked the interest in another area of skin healing. A study is underway that looks at Celadrin's effect in reducing wrinkles in the skin. By calming the skin and halting inflammation - which promotes the effects of aging - we can reduce fine lines and wrinkles.
How Celadrin Works
Celadrin works similar to, but much more dramatically than, the fatty acids EPA and DHA from fish oils. Fatty acids provide many vital, beneficial effects for the immune and inflammatory responses of the body. Various fatty acids induce changes in cell membranes and the responsiveness of the membrane to certain immune factors. They also play a role in suppressing inflammatory cell functions, decreasing cartilage breakdown (which triggers cell death) and, like NSAIDs, reduce the inflammatory activities of the Cox-2 enzyme.
The esterified (meaning they are stable and do not react with oxygen) fatty acids present in Celadrin have pronounced anti-inflammatory effects, such as the inhibition of inflammation in endothelial cells (thin cells that line the inside of some body cavities) and decreasing the pro-inflammatory effects of other fatty acids like arachidonic acid. The special fatty acids found in Celadrin have also been shown to reduce the production of the negative immune factor IL-6 and to control the immune factors responsible for inflammation. This alone could explain some effects of Celadrin, such as reduction of pain in joints affected by osteoarthritis. These anti-inflammatory functions are very important in preventing further tissue and joint damage while promoting healing. Additionally, the molecules found in Celadrin may play a role in the lubrication of an affected joint. This action, combined with anti-inflammatory effects, explains some of the significant improvements in mobility and function. Such combined effects would appear to be occurring through the application of Celadrin cream in psoriasis. Also, these special fatty acids have been shown to reduce skin inflammation, while providing a sustained moisturizing effect at the site of psoriasis.
Celadrin also works by inhibiting arachidonic acid, one of the main promoters of the inflammatory cascade of immune factors, by inhibiting 5-lipoxygenase - another mediator of inflammation. It may also alter cellular membranes, protecting them from the action of inflammatory cytokines or reducing the secretion of inflammatory cytokines and CRP.
Is Cetyl Myristoleate the same as Celadrin?
No, Cetyl Myristoleate (CMO) is a single carbon-based, fatty acid ester that has not been scientifically validated. The results of one study on CMO, using a small sample of mice, have not been replicated in a scientific setting. A most recent study published in September of 2002 in Pharmacological Research attempted to replicate this study design and protocol and found the injection of a human equivalent level of approximately 24,000 mg daily of CMO did not show a significant difference compared to the placebo group. The Physician's Desk Reference for Nutritional Supplements states that there is no credible support for claims that CMO is effective in arthritis.
Chondroitin (pronounced con-droy-tin) sulphates are natural body lubricants that provide cartilage with its elasticity and provide protection for bones in contact with one another, another shock absorber. By halting the breakdown of old cartilage and stimulating the production of new cartilage, chondroitin sulphate is an effective treatment for the protection of joints. Like glucosamine sulphate (see below), many studies have confirmed the action of chondroitin. Long-term, placebo-controlled, double-blind studies performed in Europe found that chondroitin sulphate reduced pain, and that damage to cartilage from arthritis was repaired to a significant degree within as little as three months. Again, even after the study subjects stopped taking chondroitin, they experienced lasting effects into the post study evaluation period.
DHEA is reduced in those individuals under stress and particularly in those with autoimmune disorders. Studies show that DHEA reduces the number of attacking antibodies and therefore helps to control autoimmune disorders. DHEA is often very low in Lupus patients. Research using DHEA in an unusually high dose of 200 milligrams per day reduced the symptoms of Lupus significantly. Caution: 200 milligrams per day should not be consumed without a physician's guidance. Use of DHEA is also cautioned for those with certain cancers because it may convert into testosterone and/or estrogen in the body.
At the beginning of the last century, European researchers discovered Devil's claw in Namibia, the former South West Africa. It was used as a folk remedy for the aged until it was proven to have therapeutic benefits in treating arthritic symptoms. Many new studies have confirmed Devil's claw as a potent anti-inflammatory. The active ingredient in Devil's claw, standardized harpagosides, was studied in 50 patients suffering with arthritis; results found that arthritis symptoms and severity of pain were markedly decreased. Controlled clinical research in Europe compared the efficacy of a standard anti-arthritic drug, phenylbutazone, with that of Devil's claw. The results revealed Devil's claw to be more effective in reducing pain and inflammation, without the unpleasant side effects associated with the drug.
fatty acids (EFAs) form the lipid layer of all cells in the body and control the development of the brain, eye and nervous system. They also regulate both good and bad prostaglandins that promote smooth muscle contractions and influence hormones. Omega-3 fatty acids are abundant in cold-water fish: herring, mackerel, salmon and tuna; and flaxseed and walnut oils. Omega-6 fatty acids are found in supermarket canola, sunflower and safflower oils, as well as in the food supplements evening primrose, borage and black current seed oils.
Omega-6 oils should be further classified as good or bad Omega-6 oils. Those containing Gamma-linolenic Acid (GLA) including evening primrose, borage and black current are good, anti-inflammatory oils, whereas canola, sunflower and safflower, when highly refined or eaten in excess, promote inflammation making them "bad." Our diets are predominantly high in the Omega-6 oils found in highly processed foods such as margarines and supermarket vegetable oils. Processed foods should be eliminated from your diet. Instead add fresh, unrefined foods rich in fatty acids. Those with inflammatory and/or autoimmune diseases will be the first to notice how effective this simple diet change can be in the reduction of their symptoms.
Early research has shown that fatty acids reduce the level of pain stimulators, and researchers have suggested that EFA supplementation is useful in decreasing the pain associated with osteoarthritis. EFA supplementation can help chronic inflammatory degenerative diseases of joints, such as osteoarthritis, by slowing destruction and damage to cartilage and joints; decreasing inflammation and preventing inflammatory-induced destructive processes from occurring; and possibly affecting levels of pain stimulators.
Gamma-linolenic Acid (GLA) Reduces Inflammation and Stiffness
Dr. Marya Zilberberg, in her review of close to 40 clinical papers on GLA, notes that GLA consistently reduces inflammation and joint stiffness without any of the serious side effects associated with pharmaceutical drugs. "We saw about a 60 to 65 percent reduction in morning stiffness for these patients," said Zilberg. "In other words if you have two hours of morning stiffness, there is a 1.5 hour reduction compared to a 6.7 minute reduction with a fake pill. It is an extremely striking difference."
This is good news for those with arthritis and inflammatory disorders who see morning stiffness as the most debilitating effect of their disease. "If you were to ask an arthritis patient about morning stiffness, you would find that it is an extremely important indicator of how their disease is doing," said Zilberberg. These results demonstrate the importance of long-term supplementation with large doses of GLA from borage or evening primrose oil for osteoarthritis and rheumatoid arthritis.
GLA Reduces the Use of NSAIDs: Recent research suggests that use of GLA reduces the immune factors that promote inflammation and joint tissue injuries. It is important to decrease these dangerous immune factors in order to reduce cartilage damage (the event that leads to bone erosion and crippling) and joint swelling in patients suffering from rheumatoid arthritis (RA).
Supplementing with GLA not only decreases the clinical symptoms of RA, but taking GLA can reduce the side effects of NSAIDs by repairing damage to the stomach lining. Studies show that GLA protects the stomach lining from the gastric acid that could cause stomach ulcers due to repeated or overuse of NSAIDs. As early as 1988, researchers confirmed that daily supplementation with 540 mg of GLA from evening primrose oil could help patients reduce their use of NSAIDs and there-fore protect their stomach linings. At the beginning of the study, 100 percent of patients were on their full NSAID dosage; after three months of supplementing with evening primrose oil, 70 percent of patients were still taking NSAIDs, and after six months, only 30 percent of patients were still taking NSAID at full dosage. This is a remarkable 70 percent reduction in patients using NSAIDs.
GLAs and Rheumatoid Arthritis: The Omega-6 fatty acid GLA found in evening primrose oil and borage oil is useful in the management of rheumatoid arthritis; it reduces pain and inflammation. Arachidonic acid (found primarily in organ and red meat, eggs and dairy products) produces inflammatory compounds. Supplementing with GLA-rich evening primrose oil or borage oil helps to reduce the inflammatory by-products from arachidonic acid. GLA helps to suppress the inflammatory immune cells and the synovial cell proliferation in inflamed synovial tissue; this will help decrease inflammation and pain. In clinical trials, GLA has been shown to replace pharmaceutical drugs as an NSAID substitute and, in fact, might function as a disease-modifying anti-rheumatic drug.
GLA for Juvenile Rheumatoid Arthritis: Data from a recent study conducted at the Shriners Hospital for Children in Springfield, Massachusetts found that borage oil can benefit children with Juvenile Rheumatoid Arthritis (JRA). Preliminary data from the study was presented by lead researcher Deborah Rothman, MD, PhD, during the Annual Meeting of the American College of Rheumatology in Boston. In her research, Dr. Rothman found that the effects of borage oil were strongest for patients with polyarthritis.
The use of borage oil in cases of JRA may allow some patients to reduce their dosage of standard medications such as NSAIDs or corticosteroids. Children with rheumatic disease receiving long-term corticosteroids are at high risk of developing osteo-porosis and infections. Reduction of symptoms may be observed after one month of supplementation. The full effects of GLA supplementation are seen over longer periods.
Fish Oils (Omega-3 EPA and DHA)
The first scientific paper describing the use of fish oil for treating rheumatoid arthritis was published in the 18th century. Since then, laboratory and clinical studies have revealed the beneficial effects of fish oil on various forms of arthritis. The benefits were attributed to the Omega-3 fatty acids EPA and DHA. EPA and DHA are incorporated into the cellular membranes and compete with arachidonic acid for the enzymes responsible for the production of anti-inflammatory prostaglandins.
Eicosapentaenoic acid (EPA) and Docosahexaenoic Acid (DHA) are found in high amounts in cold-water fish. EPA and DHA can also be converted from flaxseed oil, albeit in poor amounts. It is estimated that the conversion rate of flaxseed oil to EPA and DHA is somewhere around 11 percent, meaning you would have to consume a lot of flaxseed oil to get the equivalent amount of DHA and EPA found in fish oils. DHA and EPA have powerful anti-inflammatory properties. Eat at least 3 to 5 servings of salmon, herring, mackerel or tuna per week. If you are unable to eat fish or dislike the taste, use pharmaceutical grade fish oil capsules from wild salmon or small fish including sardine, mackerel or herring. Michael Murray, N.D. was one of the experts who coined the term "pharmaceutical grade fish oil." In order for fish oil to be pharmaceutical grade, it must possess the following characteristics:
- It must be manufactured in a certified GMP-facility (Good Manufacturing Practices, which are governed by strict regu-latory rules) approved for pharmaceutical products.
- It must be manufactured according to pharmaceutical standards that include quality control steps to ensure the product is free from lipid peroxides, heavy metals, environmental contaminants and other harmful compounds.
- It must provide at least a 60 percent concentration of the most active long-chain Omega-3 fatty acids (EPA and DHA).
- The ratio of Omega-3 fatty acids to arachidonic acid must be greater than 50:1.
- It must contain the optimal amount of natural vitamin E as a preservative.
- Studies show that Omega-3s decrease inflammation and degradation and help to prevent the cartilage damage that occurs in the joints. This can slow the progression of degenerative joint diseases, such as osteoarthritis.
EPA and DHA reduce the formation of bad prostaglandins and regulate immune factor production, which controls how long, how fast and how much the immune system acts or reacts. EPA produces the anti-inflammatory prostaglandins (good guys). Fish oils improve joint mobility and reduce the severity of pain and inflammation without any short- or long-term side-effects.
Abnormalities of fatty acid composition in synovial fluid in the joints have been documented in rheumatoid arthritis patients. In a 1999 study of 39 arthritic patients, synovial cell fluid samples were obtained from nine of the patients. Decreased levels of EPA and total Omega-3 fatty acids were observed in the blood and joint fluid of patients with rheumatoid arthritis. The researchers concluded that the fatty acid pattern found in those who suffer from rheumatoid arthritis (decreased levels of Omega-3s) may explain the beneficial effect of fish oil.
A 1998 review of the research confirmed the beneficial effects of fish oil in the treatment of arthritis. Fish oil reduces arthritis symptoms such as pain, number of affected joints and morning stiffness in a dose-dependent manner. Clinical benefits were seen after twelve weeks, with a dosage of 3 g of EPA and DHA per day.
It also appears that fish oil will help arthritis sufferers reduce the amount of NSAIDs needed, and some patients may be able to discontinue use completely. The first study of fish oil and RA patients examined NSAID requirements in 37 of 64 patients who were given fish oil at a dose of 1.7 g per day of EPA and 1.1 g per day of DHA in a randomized, double-blind study. After six weeks of therapy, patients were advised to reduce their NSAID dose slowly. At 12 months, all fish-oil-treated patients were crossed over to a fake pill and assessed again three months later. At the three-month mark, a 41 percent reduction in NSAID usage was achieved. Overall, patients taking fish oil had a dramatic reduction in their symptoms.
Combining EPA and GLA
Some research has studied the use of EPA and GLA together and their impact on reducing pro-inflammatory substances. A study at Wake Forest University School of Medicine found that patients supplementing with a combination of EPA and GLA reduced production of pro-inflammatory substances. A research review in Lipids, conducted at the University of Southampton, England noted that taking EPA and GLA supplements decreased the production of the pro-inflammatory immune factors that cause swelling, pain, redness and heat in the joints.
Touted as the "Arthritis Cure," glucosamine (pronounced glue-cose-a-mean) sulphate has been shown, in more than a dozen human trials, to be as good as or better than non-steroidal anti-inflammatory drugs (NSAIDs) in controlling pain and inflammation. Glucosamine normalizes cartilage metabolism while stopping its breakdown and acts as a shock absorber by lubricating and repairing joint tissue. It is an important constituent of bone and cartilage, skin, hair and nails. Several studies have shown that doses of glucosamine sulphate reduce the pain and inflammation caused by arthritis-induced joint destruction. Researchers around the world have compared the effectiveness of glucosamine to the common pain reliever (ibuprofen, Advil®, Motrin® and Nuprin®, etc.). Double-blind, placebo-controlled studies verified that glucosamine was dramatically better at controlling both pain and inflammation than ibuprofen. Pain and inflammation were reduced even after the glucosamine was no longer consumed. In addition, glucosamine has the amazing ability to aid the rebuilding process of the cartilage matrix that makes up our joint tissue.
Celadrin and Glucosamine Combined
Use Celadrin to stop the inflammatory process that is causing joint destruction and add glucosamine sulphate to repair the damage that has already occurred. Celadrin is effective at halting the joint-damaging process (whether due to RA or OA), while glucosamine can repair damage already done to those joints affected. Celadrin works by providing continuous lubrication and allowing the cell membrane to repel inflammatory messengers from the immune system. It also stops the cascade of inflammation and the assaults on the membrane, which cause stiffness. Celadrin helps glucosamine perform faster and more efficiently in building joint cartilage. The dual action of Celadrin and glucosamine will provide rapid joint cushioning, quickly alleviate inflammation, build cartilage and restore the entire joint area. Cartilage repair usually begins within two months. Spectacular results have been experienced by those individuals with RA who have adopted the combination treatment.
GREEN-LIPPED MUSSEL EXTRACT
Green-lipped mussel (Perna canaliculus) is a New Zealand shell-fish; an extract from this mollusk has been shown to inhibit inflammation in cases of rheumatoid arthritis and osteoarthritis. Not all research using green-lipped mussel for OA and RA has demonstrated therapeutic benefits, but some has been positive.
In one trial, both freeze-dried powder and lipid extract of green-lipped mussel were effective at reducing symptoms in 70 percent of people with OA and 76 percent of people with RA. A similar study of people with either OA or RA showed green-lipped mussel extract reduced pain in 50 percent and 67 percent of the patients respectively, after three months of supplementation. In 1986, stabilized dried mussel extracts became available.
Earlier studies had found no beneficial effect of green-lipped mussel extract on arthritis, but all used preparations that had not been stabilized, a fact that may help explain some of the discrepancies in the research. One recent animal study compared the two forms and found a stabilized lipid extract to be significantly more effective than a non-stabilized extract at inhibiting inflammation. Because both forms are currently available on the market, check the label to see which one you are using.
One animal study found that green-lipped mussel extract also significantly reduced stomach ulcers resulting from taking NSAIDs. In a double-blind study of people with asthma, supplementation with a proprietary extract of New Zealand green-lipped mussel (Lyprinol) twice a day for eight weeks significantly decreased daytime wheezing and improved airflow through the bronchi. Those with shellfish allergies should avoid this product. Nausea was noted in some taking high doses.
According to the authors of MSM, The Natural Solution for Pain, MSM relieves pain, reduces inflammation and IL-1, reduces scar tissue formation, reduces muscle spasms and more. MSM is a major source of sulfur in humans. Sulfur is especially important for healthy joint function. It stabilizes the connective tissue matrix of cartilage, tendons and ligaments. As early as the 1930s, researchers found that arthritic patients were deficient in this essential nutrient. By simply adding sulfur to the diet, arthritis symptoms improved. Sulfur also promotes proper liver function and improves insulin's action.
Michael Murray, N.D. states that, "MSM provides significant advantages over other forms of sulfur in that it is completely safe. When people say they are allergic to sulfur, what they really mean is that they are allergic to the so-called sulfa drugs or sulfite-containing food additives. It is impossible to be allergic to sulfur as sulfur is an essential mineral."
Research reported in The Journal of Anti-aging Medicine found that when eight patients were given 2,250 mg of MSM daily and six patients were given a placebo, after six weeks of treat-ment those taking MSM indicated they had better than 80 per-cent reduction in pain.
Although it is not an anti-inflammatory, PeptAce is the most effective natural substance for lowering blood pressure and is recommended in the Heart Disease section. PeptAce is a mixture of 9 small peptides (proteins) derived from bonito (a member of the tuna family). It works to lower blood pressure by inhibiting ACE (angiotensin converting enzyme), thereby inhibiting the formation of angiotensin II, a substance that increases both the fluid volume and the degree of constriction of the blood vessels. If we use a garden hose model, angiotensin II would be similar to pinching off the hose while turning up the faucet full blast. By inhibiting the formation of this compound, anti-ACE peptides relax the arterial walls and reduce fluid volume. PeptAce fish peptides exert the strongest inhibition of ACE reported for any naturally occurring substance available.
Three major clinical studies have been conducted with PeptAce fish peptides. The material appears to be effective in about two-thirds of people with high blood pressure - about the same percentage that many prescription drugs achieve. The degree of blood pressure reduction in these studies was quite significant, typically reducing the systolic by at least 10 mm Hg and the diastolic by 7 mm Hg in people with borderline and mild hypertension. The typical dosage is three 500-mg capsules daily. No side effects were reported in the clinical studies, and a safety study showed no side effects with dosages as high as 30 g daily.
PeptAce fish peptides do not affect blood pressure in people without hypertension, do not interact negatively with potassium and have no adverse drug interactions, so they can be used in combination with conventional anti-hypertensive drugs.
Esteemed by Ayurvedic practitioners for centuries, turmeric contains anti-inflammatory curcuminoids. These reduce pain by blocking the enzymes that cause inflammation. Turmeric inhibits the breakdown of arachidonic acid. Several double-blind studies have shown dramatic improvements in symptoms experienced by rheumatoid arthritis sufferers. Turmeric is also an antioxidant. Researchers at the University of California found that curcumin, in both low and high doses, reduced the inflammatory immune factors IL-1 and IL-6 secreted by microglia cells. This finding means turmeric shows great promise for the prevention of Alzheimer's and memory decline.
A study published in the June 26, 2002 Journal of the American Medical Association suggested that vitamins E, C, beta-carotene and a general multi-vitamin with minerals may help protect people against cognitive and memory decline. Vitamins E and C are powerful anti-inflammatory nutrients inhibiting IL-1 and IL-6, so it makes sense that they would protect our brains from injury or inflammatory assault. Vitamin A helps to increase the good immune factors that turn off the inflammatory and pain-causing immune factor IL-1. Vitamin D, the only vitamin that acts like a hormone, reduces IL-1 and -12. Vitamin E decreases inflammatory prostaglandins that are associated with pain and inflammation. It also decreases the negative effects of stress. (Stressors cause the release of our stress hormone, cortisol. Cortisol then causes the inflammatory immune factor IL-6 to be released.) Vitamin E also increases the good immune factors that keep IL-1 and IL-6 under control.
Yes, water cushions your joints. If you are not drinking six to ten glasses of water every day, your joint cushions are dehydrated. Water helps to eliminate all of the debris left over from inflammatory reactions as well, particularly in those with asthma and allergies.
WHITE WILLOW BARK
White willow bark is nature's aspirin. It is an ancient remedy used to treat fevers and arthritic complaints. Salicin is its active ingredient. Many human studies have evaluated White willow bark's ability to rapidly relieve pain and reduce inflammation.