Life Extension Magazine®

Scientist working with undenatured type 2 collagen for immune reactions

Halt the Auto-Immune Attack of Arthritis

Undenatured type II collagen has a unique molecular structure that inhibits immune overreactions to collagen proteins. Studies show significant reductions in pain and inflammation scores when tested in those with rheumatoid and osteoarthritis.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in October 2024. Written by: Michael Downey, Health & Wellness Author.

Halt the Auto-Immune Attack of Arthritis

By the time people reach age 65, a startling 80% show X-ray evidence of osteoarthritis1—the most frequent cause of musculo-skeletal disability worldwide.1,2

Most doctors consider osteoarthritis and rheumatoid arthritis to be progressive and incurable. Side effect prone drugs only transiently soften pain and have no long-term impact on the disease itself.3,4

Conventional medical wisdom mistakenly believed that in contrast to rheumatoid arthritis—which results from an autoimmune attack on joints—osteoarthritis was simply the result of age-related “wear-and-tear.”

However, scientists now understand that, in both of these conditions, an inflammatory immune system attack on joint compounds can be triggered by exposed collagen.5

This article is about undenatured type II collagen, which has a unique molecular structure that interferes with damaging inflammation responses and helps to retrain the immune system.

Studies show that exposure to small amounts of type II chicken collagen can inhibit immune overreaction to exposed collagen proteins, substantially reducing the pain and disability of osteoarthritis4,6-8 and rheumatoid arthritis.9-12 In one study, an unheard-of 14% of patients taking undenatured type II collagen experienced complete remission of their rheumatoid arthritis!9

A unique formulation of undenatured type II collagen, UC-II®, was found in controlled studies to significantly reduce pain and increase function in arthritic dogs,6,7,13,14 horses,8 and humans.4

As you’ll learn, pain scores for osteoarthritis patients taking UC-II® decreased—in just 90 days—by a remarkable 40%!4

A New Understanding of Osteoarthritis

Cartilage, the shock-absorbing substance that lines our joints and allows them to slide smoothly, is comprised largely of a protein known as collagen. Minor damage to cartilage exposes small fibers of collagen that trigger rheumatoid arthritis—and osteoarthritis as well.

Until recently, conventional medical thinking held that these two forms of arthritis involve different pathologies.

Only rheumatoid arthritis was recognized as an inflammatory immune process—where the body’s oversensitive immune system attacks the body’s own tissues, in this case the joint linings and cartilage.

By contrast, osteoarthritis was believed to be an unavoidable result of the simple wear-and-tear of age and repeated use on joint cartilage and bone. It was assumed that joint-cushioning cartilage simply wore away, leaving the friction of increasingly painful scraping and inflammation.

The assumption that osteoarthritis is the degeneration of cartilage may have stemmed largely from the fact that this form of arthritis arises typically in the later years of life; and the number of minor cartilage traumas that can spark an immune response tend to increase as the water content of cartilage is reduced—which is indeed, age-related.

So, osteoarthritis has long been assumed to be an inevitable and incurable consequence of aging. In recent years, research has increasingly shown that immune mediated joint inflammation plays a large role in the development and perpetuation of osteoarthritis. This new understanding of the underlying cause of osteoarthritis offers new avenues for medical intervention and has even brought forth the possibility of a cure!

New research shows that the underlying pathology behind osteoarthritis is the triggering of an inflammatory immune response—similar to rheumatoid arthritis. The end result—for both forms of arthritis, scientists now realize—is activation of “killer” T-cells by exposed collagen, destruction of joint surfaces, and the accompanying pain and impaired function.9,15

For the first time, this establishes osteoarthritis as a disease progression that is not inevitable—and opens the door to the possibility of a single intervention to modulate the abnormal immune response behind both of these types of arthritis.

So let’s take a look at how scientists now see the development of osteoarthritis, and how we can re-educate the immune system to halt the progression of both types of arthritis—and reverse it!

The Immune System Cause of Joint Disease

Joints take a beating over time, with those in the weight-bearing lower half of our bodies taking the heaviest punishment. Small traumas to cartilage occur at all ages, but go unnoticed in younger individuals. In time, these traumas result in exposed fibers of collagen, a cartilage component.16

And that’s the early silent signal for a devastating chain of events.

Normally sealed off from the immune system, newly exposed microscopic collagen fibers are now mistaken as “foreign” cells.17

The body’s alarm goes off indicating a foreign invasion that triggers a complex and destructive interplay known as the complement cascade. An army of “killer” T-cells is sent to the joint, followed by the release of inflammatory cytokines, which in turn draw in more “killer” T-cells.17,18

This culminates in the release of a cell-destroying protein cluster called the membrane attack complex, or MAC.19 These MAC proteins bind themselves to cartilage-producing cells, causing them to secrete complement-component proteins, as well as other inflammatory chemicals and enzymes. Together, these secreted compounds proceed to chew up the matrix of cartilage occupying the spaces between cells.18

But the attack doesn’t end there!

Researchers found that as cartilage fibers are destroyed by the immune system, the destroyed cells release various byproducts, including fibromodulin. These damaging breakdown products directly reactivate the complement cascade—driving a vicious and continuing cycle of joint-tissue damage.18

Small, surface fibers trigger the initial immune response. Then the secondary cycle of trigger-damage eventually eats away the healthy cartilage within the joint—creating the pain, friction, and grinding known as osteoarthritis.19

To prove this chain of events is the origin of osteoarthritis, mice were bioengineered so that they lacked a key protein, without which the complement cascade (a specific set of events that set off an immune response) cannot be triggered. Following a cartilage tear—which in this special case did not trigger the normal immune-attack cascade—the mice maintained their ability to walk normally and did not suffer any osteoarthritic or immune reaction.18

Rheumatoid arthritis occurs when the immune system mistakenly identifies exposed cartilage—or other joint elements such as synovial fluid or the synovial membrane—as “enemies.”9 An inflammatory response ensues that is considered to be high-grade, which is why rheumatoid arthritis is categorized as a true autoimmune disease. As in osteoarthritis, exposed collagen triggers the complement cascade, a cyclical attack that eventually destroys the joint surfaces and normal function.

Now aware that both osteoarthritis and rheumatoid arthritis are substantial immune reactions triggered by exposed collagen,219,20 scientists sought ways to target the common immune origin of these joint-destroying diseases.

The ideal prevention would be to re-educate the immune system to differentiate between exposed collagen fibers and foreign bodies. This would inhibit overreaction to proteins normally found in joint cartilage, and prevent immune-mediated attacks on the joints.

Fortunately, a number of studies have shown that a form of a natural collagen does just that!

Protect Your Joint Health with Undenatured Type II Collagen

Until recently, osteoarthritis was simply considered to be the mechanical wearing down of cartilage with use and aging, treatable only with risky and ineffective NSAIDs and immune suppressants.
Scientists have now learned that osteoarthritis—like rheumatoid arthritis—is an abnormal immune response to exposed collagen fibers in joint cartilage.
Oral introduction of type II collagen desensitizes the immune system to collagen fibers, preventing the inflammatory response that leads to further joint destruction.
This unique intervention works by activating the natural pathway of induced oral tolerance—“short-circuiting” both osteoarthritis and rheumatoid arthritis!
Controlled clinical studies have confirmed that undenatured type II collagen uniquely inhibits arthritic joint pain, swelling, and loss of function—by blocking the disease process in both rheumatoid and osteoarthritis.

Short-Circuit Arthritis—at its Root

Because arthritis has been considered impossible to cure, standard medical treatment has focused on drugs for inflammation and pain and in some cases, immune suppressants. These pharmaceuticals include NSAIDs such as ibuprofen (Motrin®), and corticosteroids such as prednisone. They substantially increase the risk of life-threatening disorders, including obesity, kidney disease, diabetes, heart disease, and stroke.21-24 And yet, they only blunt symptoms while having no impact on the origin of the disease itself.4

So, scientists have long sought ways to short-circuit the immune response to exposed collagen.

Then, researchers came across the surprising finding that something in chicken soup exerted an anti-inflammatory activity, protecting sites of inflammation from attack. 25

When scientists later investigated type II chicken collagen, they discovered its potential to act along natural immune pathways to induce tolerance to exposed collagen.

At that time, osteoarthritis was still seen as simply the mechanical wearing down of cartilage with use and aging. So, chicken collagen was initially tested only on the known autoimmune joint condition, rheumatoid arthritis.

In a randomized, double-blind study of the effect of type II chicken collagen on 60 patients with active rheumatoid arthritis, the number of swollen and tender joints decreased in the collagen group, but not in the placebo group—within just 3 months. However, the study team observed another dramatic finding: an unheard-of 14% of those patients receiving type II chicken collagen had a complete remission of their rheumatoid arthritis!9

These findings for type II chicken collagen were confirmed with similar results in a larger trial of 274 patients with active rheumatoid arthritis.10

Scientists tested oral type II collagen on patients with juvenile rheumatoid arthritis, an especially aggressive form of this disease that begins in childhood. In just 12 weeks, 80% of the patients in the type II collagen group responded to treatment with an average reduction of 61% in the number of swollen joints, and an average reduction of 54% in the number of tender joints.11

Eventually, researchers conducted a conclusive phase III clinical trial on over 500 rheumatoid arthritis patients, which was published in the journal Arthritis Research & Therapy in 2009. They found that supplementing with type II chicken collagen resulted in reduced disease activity and beneficial effects—exerted specifically, in the words of the study authors, “through inducing oral tolerance.”12

As it became increasingly apparent that osteoarthritis—like rheumatoid arthritis—is an immune disorder, scientists began testing type II chicken collagen on this most prevalent form of joint disease.

Let’s examine the results of these breakthrough studies.

How UC-II® Induces Oral Tolerance

Researchers found that normally processed collagen exhibited no bioactivity and would not induce oral tolerance.15 Only a specific form of collagen, with its unique molecular structure, will retrain the immune system not to overreact to exposed collagen fibers. To understand this difference, let’s examine how oral tolerance is induced.

T-cells are in part, immune system watchdogs, constantly assessing the three-dimensional structure of proteins they encounter in order to distinguish between harmless “self” proteins and potentially deadly “foreign” proteins.27

If T-cells are exposed in the blood to a new protein structure—such as an unrecognized protein on separated collagen fiber—they react violently and trigger an inflammatory response to destroy what is presumed to be a disease-causing invader.28

And that deadly inflammatory attack is extended to any other collagen molecules that are subsequently encountered by the T-cells—including intact collagen in cartilage in the joint.

In fact, injecting collagen into animals is the standard procedure to create an animal model of arthritis for experiments. It sensitizes the T-cells in their blood to the collagen protein, which results in inflammation in the animal’s joints where the circulating T-cells encounter rich supplies of identical molecular structures.29 The inflammatory result is arthritis.

However, scientists have learned that it is possible to teach T-cells that the collagen molecule is a friend rather than a foe.

Rich collections of immune tissue are located in the lower end of the small intestine. Called Peyer’s patches, they act as “training centers” for the immune system, exposing T-cells to a vast variety of molecular shapes among the natural components in the food we eat. This desensitizes T-cells to new foods to avoid constant inflammatory or allergic reactions. In other words, this is the area that induces tolerance.30

Native collagen introduced into the digestive tract—rather than directly into the bloodstream—can “educate” T-cells to ignore collagen fibers when they are encountered in the joints.31 In scientific terms, the result is “induced specific oral tolerance.”32,33

This oral tolerance to collagen powerfully suppresses joint inflammation, as has been shown in numerous studies.32-35

But to induce tolerance to exposed joint collagen, the orally introduced product must be type II collagen—the same form of collagen found in the cartilage matrix—and must have the exact same three-dimensional structure.

Typical commercial processing causes collagen to become denatured. Its normal helical shape uncoils and it has as a slightly, but crucially, altered three-dimensional structure. Denatured collagen does not induce oral tolerance.32

However, undenatured type II chicken collagen retains its molecular structure, allowing it to induce oral tolerance.

Scientists found that—even in small doses—orally administered undenatured type II chicken collagen inhibits the killer T-cell attack.15,34

UC-II® is a proprietary formulation of undenatured type II chicken collagen, derived from chicken sternum cartilage, a rich source of natural collagen. UC-II® retains the original helical molecular structure of joint collagen.27 This allows the T-cells in Peyer’s patches to develop tolerance to exactly the same molecular shape as exposed collagen encountered in the joints—which will now be recognized as “self,” not “foreign,” molecules.

This unique molecular composition of UC-II® has been shown to be robust. This enables UC-II® to survive passage through the harsh conditions of the stomach and small intestine, so that it arrives finally at Peyer’s patches with its molecular structure intact.27

Studies verify that when undenatured type II collagen is introduced into the digestive tract, it induces oral tolerance to the exposed collagen inside the joint and suppresses rheumatoid and osteoarthritis.

UC-II® Modulates Osteoarthritis

Turning their attention to osteoarthritis, scientists tested UC-II®, a proprietary form of undenatured type II chicken collagen, on horses and larger dogs. These animals are, like humans, very susceptible to osteoarthritis.

Only a specific undenatured form of collagen, which maintains its unique molecular structure, can retrain the immune system not to overreact to exposed collagen fibers. To understand this crucial difference, see the box on the next page.

Dogs with osteoarthritis given UC-II® were found to exhibit significant reductions in overall pain, in pain after limb manipulation, and in lameness after physical exertion—within 90 days.6 There were no adverse side effects. When UC-II® was then withdrawn for the next 30 days, the pain and exercise-associated lameness returned.6

These findings were confirmed when a subsequent study on arthritic dogs found that UC-II® produced the same significant decrease in arthritic pain—again, within 90 days.7

A longer study found that while arthritic dogs given UC-II® were measured to experience significant improvements in pain and mobility after 30 and 60 days, they showed the greatest benefit after 120 days of supplementation. By that point, the UC-II® group was measured to have a 62% reduction in overall pain, a 78% reduction in exercise-associated lameness—and a surprising 91% reduction in pain upon limb manipulation!13

A later placebo-controlled study confirmed these observations. After 120 days, dogs treated with UC-II® were assessed to have a 77% reduction in overall pain, an 84% reduction in exercise-associated pain, and an 83% reduction in pain upon limb manipulation. No adverse effects were found—even after a thorough check of liver, kidney, and heart function.26

A longer, more precision-based study was undertaken in 2011, using a high-tech ground force plate employing a special piezoelectric sensor. This apparatus allowed researchers to measure with a high degree of accuracy, the exact force and weight that dogs placed on each arthritic limb. Dogs given the undenatured UC-II® formulation were able to place more weight on sore limbs and use them more naturally, relative to those given either placebo or the combination of chondroitin-plus-glucosamine. Monthly tests of kidney and liver function, pulse rate, temperature, and weight found no adverse effects.The data from the groundforce plate study showed that dogs in the UC-II® only group showed continued improvement after 150 days, at which time supplementation was discontinued.154

In a large, placebo-controlled study, researchers administered oral doses of UC-II® to horses. They measured reductions of 88% in overall pain, and 78% in pain during limb manipulation among horses given UC-II®. These benefits were seen after 150 days of supplementation.8

Studies demonstrated that UC-II® alone produced much greater results in relieving arthritis in dogs and horses than the combination of chondroitin and glucosamine sulfate alone.8,13 However, the same researchers found that combining UC-II®, with chondroitin and glucosamine sulfate produced the greatest benefits, substantially alleviating pain and improving function.15 This suggests the possibility that humans may be found to benefit from the dual action of these two treatments together. While impressive evidence indicates that undenatured type II collagen inhibits processes responsible for the progression of arthritis, the glucosamine-and-chondroitin combination has previously been shown to repair damaged joints.10,14 Scientists then shifted their focus to the effect of UC-II® on osteoarthritis in humans.

Extinguishing Arthritis at Its Source

Today, 52 million Americans live with some form of arthritis,36 with its debilitating joint pain and impairment. The standard medical treatment for arthritis has been anti-inflammatory and pain drugs, including NSAIDs such as ibuprofen (Motrin®), as well as corticosteroids such as prednisone. Over 46% of those diagnosed with osteoarthritis are prescribed NSAID therapy.37

At best, these medications partially blunt the symptoms. At worst, they substantially increase the risk of life-threatening disorders, including obesity, kidney disease, diabetes, heart disease, and stroke.21-24 And they compromise the immune system.18 But for a long time, medical science offered no treatment that would have a fundamental impact on the origin of the disease itself.4

However, both rheumatoid arthritis and osteoarthritis are now understood to be immune disorders—massive immune system attacks triggered by the minor traumas to joint cartilage that result in exposed collagen fibers.

Scientists sought ways to activate induced specific oral tolerance to exposed collagen. Achieving induced specific oral tolerance requires involvement of the immunological pathway, the “immune learning center” within our digestive tract. Here, the immune complement system is trained to differentiate correctly between “self” and “foreign” cells.

Through induced specific oral tolerance, it is possible to reprogram the immune system to suppress reactivity to a specific antigen—to teach it to tolerate the harmless substance. The immune system’s ability to acquire tolerance by oral administration of the antigen is likely rooted in mankind’s early evolution. It may have evolved to prevent hypersensitive reactions to food proteins, which is in keeping with the fact that this immunological pathway is situated within the digestive tract.

Inducing specific oral tolerance to exposed collagen requires finding, and then introducing to the body through the immune system’s desensitization area within the digestive tract, a substance with precisely the same molecular shape as the collagen fiber molecules currently being identified as “foreign.”

Unlike regularly processed type II collagen, the undenatured form maintains its molecular shape.

Scientific studies have confirmed that undenatured type II collagen effectively reprograms the immune system to recognize the proteins normally found in joint cartilage to be harmless “self” cells.30-32 This significantly relieves symptoms of both rheumatoid arthritis9-11and osteoarthritis.4-9,13,14

Targeting Osteoarthritis in Humans

Evidence had already established the effectiveness of undenatured type II collagen in inhibiting the symptoms of rheumatoid arthritis in humans. However, it would be necessary to separately establish this unique ability of UC-II® in human cases of osteoarthritis. To achieve this, researchers employed a stringent study protocol: a randomized, double-blind, clinical study on humans.

In a study of this type, 52 adults suffering from osteoarthritis with an average age of 59 were randomly assigned to receive daily either two 20 mg capsules of UC-II®, or a combination of four 375 mg capsules of glucosamine plus four 300 mg chondroitin sulfate. All patients were assessed at 30-day intervals.4

The researchers found that in just 90 days, UC-II® provided “significant enhancement in daily activities, suggesting an improvement in their quality of life.”4

In the same trial, the researchers employed the standardized WOMAC (Western Ontario McMaster Osteoarthritis Index) scale to accurately assess symptoms. They concluded that 40 mg a day of UC-II® reduced osteoarthritis symptoms assessed by the WOMAC scale by 33%—in only 90 days. By comparison, the combination of 1,500 mg a day of glucosamine and 1,200 mg a day of chondroitin sulfate reduced WOMAC scores in the same period by only 14%.4

The team of scientists then used the Visual Analog Scale (VAS)—which is used to assess pain—to corroborate these results. Using this measure, they found pain scores decreased by 40% for the UC-II® group, while pain scores for the glucosamine/chondroitin group decreased just 15%.4

Finally, using the Lequesne’s Functional Index—a measure specifically of pain during daily activities, such as walking—the study team found that UC-II® reduced the score for this type of pain by 20%, while the combination of glucosamine plus chondroitin lowered the score by only 6%.4

All results were observed in just 90 days.

This compelling human research crowns a series of studies indicating that undenatured type II cartilage induces oral tolerance to exposed collagen, inhibiting the immune response that inflames joints and further degrades joint cartilage.

Summary

Recent research has revealed that cartilage erosion caused by wear-and-tear is not the immediate cause of osteoarthritis—it is only the initial trigger.

Scientists now know that osteoarthritis, like rheumatoid arthritis, is an abnormal immune-system overreaction to exposed collagen fibers in joint cartilage.

Until this discovery, the standard treatment has been risky NSAIDs and immune suppressants, which have no effect on the underlying cause of this immune reaction.

Oral introduction of type II chicken collagen desensitizes the immune system to collagen fibers, “teaching” inflammatory killer T-cells to ignore exposed collagen in the joints.

This unique intervention works by activating induced oral tolerance, the natural pathway that effectively “short-circuits” the immune response behind arthritis—halting disease activity.

Controlled clinical studies indicate that undenatured type II collagen uniquely inhibits inflammatory joint pain, joint swelling, and impaired function in both rheumatoid and osteoarthritis.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

Shamir L, Ling SM, Scott WW Jr, et al. Knee x-ray image analysis method for automated detection of osteoarthritis. IEEE Trans Biomed Eng. 2009 Feb;56(2):407-15.
Zhang Y, Niu J, Kelly-Hayes M, Chaisson CE, Aliabadi P, Felson DT. Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly, The Framingham Study. Am J Epidemiol. 2002;156:1021-7.
Scott DL, Berry H, Capell H, et al. The long-term effects of non-steroidal anti-inflammatory drugs in osteoarthritis of the knee: a randomized placebo-controlled trial. Rheumatology (Oxford). 2000 Oct;39(10):1095-101.
Crowley DC, Lau FC, Sharma P, et al. Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a clinical trial. Int J Med Sci. 2009;6(6):312-21.
Goldring SR, Scanzello CR. Plasma proteins take their toll on the joint in osteoarthritis. Arthritis Res Ther. 2012 Mar 5;14(2):111.
Deparle LA, Gupta RC, Canerdy TD, et al. Efficacy and safety of glycosylated undenatured type-II collagen (UC-II®) in therapy of arthritic dogs. J Vet Pharmacol Ther. 2005 Aug;28(4):385-90.
Peal A, D’Altilio M, Simms C, et al. Therapeutic efficacy and safety of undenatured type-II collagen (UC-II®) alone or in combination with (-)-hydroxycitric acid and chromemate in arthritic dogs. J Vet Pharmacol Ther. 2007 Jun;30(3):275-8.
Gupta RC, Canerdy TD, Skaggs P, et al. Therapeutic efficacy of undenatured type-II collagen (UC-II®) in comparison to glucosamine and chondroitin in arthritic horses. J Vet Pharmacol Ther. 2009 Dec;32(6):577-84.
Trentham DE, Dynesius-Trentham RA, Orav EJ, et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993 Sep 24;261(5129):1727-30.
Barnett ML, Kremer JM, St Clair EW, et al. Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 1998 Feb;41(2):290-7.
Barnett ML, Combitchi D, Trentham DE. A pilot trial of oral type II collagen in the treatment of juvenile rheumatoid arthritis. Arthritis Rheum. 1996 Apr;39(4):623-8.
Wei W, Zhang L-L, Xu J-H. A multicenter, double-blind, randomized, controlled phase III clinical trial of chicken type II collagen in rheumatoid arthritis. Arthritis Research & Therapy. 2009;11:R180.
D’Altilio M, Peal A, Alvey M, et al. Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with glucosamine and chondroitin in arthritic dogs. Toxicol Mech Methods. 2007;17(4):189-96.
Gupta RC, Canerdy TD, Lindley J, et al. Comparative therapeutic efficacy and safety of type-II collagen (UC-II®), glucosamine and chondroitin in arthritic dogs: pain evaluation by ground force plate. J Anim Physiol Anim Nutr. Epub 2011 May 30.
Bagchi D, Misner B, Bagchi M, et al. Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a mechanistic exploration. Int J Clin Pharmacol Res. 2002;22(3-4):101-10.
Heinegard D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol. 2011 Jan;7(1):50-6.
Cohen ES, Bodmer HC. Cytotoxic T lymphocytes recognize and lyse chondrocytes under inflammatory, but not non-inflammatory conditions. Immunology. 2003 May;109(1):8-14.
Wang Q, Rozelle AL, Lepus CM, et al. Identification of a central role for complement in osteoarthritis. Nature Medicine. Nov 6 2011.
Adatia A, Rainsford KD, Kean WF. Osteoarthritis of the knee and hip. Part I: aetiology and pathogenesis as a basis for pharmacotherapy. J Pharm Pharmacol. 2012 May;64(5):617-25.
Tarkowski A, Klareskog L, Carlsten H, Herberts P, Koopman WJ. Secretion of antibodies to types I and II collagen by synovial tissue cells in patients with rheumatoid arthritis. Arthritis Rheum. 1989 Sep;32(9):1087-92.
Singh G, Wu O, Langhorne P, Madhok R. Risk of acute myocardial infarction with nonselective non-steroidal anti-inflammatory drugs: a meta-analysis. Arthritis Res Ther. 2006;8(5):R153.
Thomas MC. Diuretics, ACE inhibitors and NSAIDs—the triple whammy. Med J Australia. Feb 2000;172(4):184-5.
Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ (Clinical research ed.) June 2006;332(7553):1302-8.
Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti inflammatory drugs: network meta-analysis. BMJ (Clinical research ed.) 2011 Jan 11;342:c7086.
Rennard BO, Ertl RF, Gossman GL, Robbins RA, Rennard SI. Chicken soup inhibits neutrophil chemotaxis in vitro. Chest. 2000 Oct;118(4):1150-7.
Gupta RC, Barnes M, Minniear J. et al. Pain reduction measured by ground force plate in arthritic dogs treated with type-II collagen. Presented at Society of Toxicology 48th Annual Meeting, March 2009. 108(1);Abstract 769:159.
Cremer MA, Rosloniec EF, Kang AH. The cartilage collagens: a review of their structure, organization, and role in the pathogenesis of experimental arthritis in animals and in human rheumatic disease. J Mol Med (Berl). 1998 Mar;76(3-4):275-88.
Corthay A, Backlund J, Broddefalk J, et al. Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis. Eur J Immunol. 1998 Aug;28(8):2580-90.
Meyer O. Oral immunomodulation therapy in rheumatoid arthritis. Joint Bone Spine. 2000;67(5):384-92.
Park KS, Park MJ, Cho ML, et al. Type II collagen oral tolerance; mechanism and role in collagen-induced arthritis and rheumatoid arthritis. Mod Rheumatol. 2009;19(6):581-9.
Min SY, Park KS, Cho ML, et al. Antigen-induced, tolerogenic CD11c+,CD11b+ dendritic cells are abundant in Peyer’s patches during the induction of oral tolerance to type II collagen and suppress experimental collagen-induced arthritis. Arthritis Rheum. 2006 Mar;54(3):887-98.
Weiner HL. Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today. 1997 Jul;18(7):335-43.
Zhu P, Li XY, Wang HK, et al. Oral administration of type-II collagen peptide 250-270 suppresses specific cellular and humoral immune response in collagen-induced arthritis. Clin Immunol. 2007 Jan;122(1):75-84.
Nagler-Anderson C, Bober LA, Robinson ME, Siskind GW, Thorbecke GJ. Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7443-6.
Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005;206:232-59.
Available at: http://www.cdc.gov/nchs/fastats/arthrits.htm. Accessed April 3, 2012.
Lanas A, Garcia-Tell G, Armada B, Oteo-Alvaro A. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis. BMC Med. 2011 Apr;14(9):38.