Increased intestinal permeability—also known as "leaky gut"--is a root cause of many autoimmune reactions. Increased permeability means that potential antigens from inside the gut can pass into the blood and activate the immune system. These activations and reactions are a key trigger of many bone and joint problems, explained Dr. Larson, a chiropractor and functional medicine practitioner in Encinitas, CA.

He is one of a rising number of clinicians from diverse disciplines who have recognized the role of autoimmune reactions in the etiology of a wide range of seemingly unrelated disorders.

The good news is that it is now possible to detect autoimmune antibodies in blood long before chronic autoimmune reactions cause end-stage tissue damage. This opens a wide window for interventions that can ameliorate autoimmunity and, ideally, avert years of suffering.

A Dx is Just the Beginning

Biomarkers of autoimmunity typically show up in blood several years before disease processes manifest as symptoms. "We can assess the antibodies very early on and perhaps prevent an autoimmune condition from manifesting," says Dr. Larson in an online course on autoimmunity now available on HPC's new Holistic Education Exchange website.

Patients with joint or bone disorders should be evaluated for leaky gut, advised Dr. Larson. He stressed that diagnosis of a condition like osteoporosis or osteoarthritis is not an endpoint. "It's the beginning of our investigation of why a disease process is manifesting. Often it's autoimmune in origin. By knowing that, it creates a therapeutic branch point, where in some individuals with osteoporosis we need to go down the immune system pathway rather than looking at other possible origins of the disease. "

A number of important biomarkers of autoimmunity correlate strongly with bone, joint and connective tissue disorders:

• Collagen Complex is associated with various forms of arthritis, Goodpasture's syndrome and type 1 bullous systemic lupus erythematosus (SLE).
• Arthritic Peptide is associated with mixed connective tissue disease, osteoarthritis, and rheumatoid arthritis.
• Fibulin is associated with osteoarthritis, and interestingly, atherosclerosis.

As a group, the fibulins play a central role in the assembly and stabilization of extracellular matrix structures. They regulate organogenesis, vasculogenesis, hemostasis, fibrogenesis, and also tumor formation.

Fibulin-4 appears to be an important autoantigen associated with osteoarthritis. In one study, it was identified in 15% of serum samples from patients with OA and in 5% of serum samples from patients with RA (Xiang Y, et al. J Immunol. 2006: 196; 3196-3204)

Osteoporosis, Arthritis & Celiac Disease

One factor that's probably under-appreciated is the inter-relationship between osteoporosis, arthritis and celiac disease.

Celiac is clearly associated with abnormal intestinal permeability, which may contribute to osteoporosis by causing changes in bone metabolism and electrolyte balance. But the link may be even more direct: Celiac-associated autoantibodies may actually attack bone and joint tissue.

More than a decade ago, Dr. Emilia Sugai and her research team in Buenos Aires observed that, "Osteopenia and osteoporosis are well-known complications detected in celiac disease patients." They studied autoantibodies in the blood of people with celiac, and found that many had antibodies targeting bone tissue transglutaminases.

"Based on the localization of the immunoreactivity, we speculate that they might have an active role in the pathophysiology of celiac disease-associated bone complications," the authors noted (Sugai E, et al. J Clin Immunol. 2002: 22(6): 353-362). 

As early as the mid 1980s, researchers around the world began to identify the inverse correlations between high titers of anti-bone antibodies, and bone mineral density: the higher the titers, the lower the BMD, explained Dr. Larson.

Intestinal inflammation in celiac disease is driven by the gluten fraction of wheat proteins. Deamidation or cross-linking of gluten peptides by tissue transglutaminase (tTG), a key autoantigen in celiac disease, creates potent T cell stimulatory peptides (Dieterich W, et al. Gut. 2006. 55: 478-484).

"Celiac disease is a major cause of bone mineral loss. It is an underlying cause of osteoporosis in some cases. If you have a patient with osteoporosis, why not also check for celiac? You may find a very meaningful trigger. If you remove gluten from the diet, the biomarkers and the bone loss may improve," says Dr. Larson.

Old Ideas, New Possibilities

Autoantibodies targeting bone and joint tissue play a role not only in osteoporosis but in various forms of arthritis as well. This is actually an old concept now being validated via new immunological testing techniques. The notion that gut-derived factors could provoke rheumatic disease was first proposed by Dr. Rea Smith, a pioneering Navy surgeon, back in 1922!

Since then the link between inflammatory bowel disease and arthritis has become well established, and antigens derived from the gut have been implicated in reactive arthritis, ankylosing spondylitis, and rheumatoid arthritis.

Researchers have identified a number of components within bone and joint tissue that become immune system targets. These include Phex protein and Calreticulin. The latter is a frequent target of serum autoantibodies in various diseases. However, IgA isotypes of anti-CRT antibodies have only been detected in people with Celiac and some hepatic diseases.

Compared with non-rheumatoid controls, people with rheumatoid arthritis show consistently higher levels of IgG antibodies to a host of antigens including: rheumatoid factor (RF), Arthritis peptide, CCP, mitochondrial dehydrogenase, collagen, mycobacteria, mycoplasma, C. pneumoniae, HSP-60. They also have higher TNF alpha production.

Osteoarthritis patients show consistently higher levels of IgG antibodies to rheumatoid factor, rheumatoid factor peptide, to fibulin and Y enterocolitica (Vojdani A. Int J Immunopathol Pharmacol. 2008. 21(2): 267-278).

Raised titers of IgG and IgM anti-CRT antibodies have been seen in patients with SLE, subacute cutaneous and neonatal lupus, rheumatoid arthritis (RA), Sjögren's syndrome (SS), complete congenital heart block, mixed connective tissue disease (MCTD), hepatocellular carcinoma, and a number of parasitic infections (Sanchez D, et al. J Autoimmunity. 2003: 383-392).

People with celiac will often show increased antibody titers against four types of collagen: collagens I, III, V, and VI. These tissue transglutaminase antibodies appear to play a central role in both perpetuating intestinal inflammation and triggering systemic symptoms outside the intestines (Dieterich W, et al. Gut. 2006. 55: 478-484).

In many celiac patients, skeletal symptoms will presage bowel symptoms by as many as 3-15 years, according to a case series published by Bourne and colleagues at St. Bartholomew's Hospital, London (Bourne JT, et al. Annals of Rheumatic Diseases. 1985; 44: 592-598).

Squelching Disease Before it Happens

Autoimmunity is the result of a triad of factors: genetic predispositions, compromise to intestinal barrier, and exposure to triggers—especially dietary and environmental antigens, explained Dr. Larson.

The idea that food-related antigens play a role in arthritis or osteoporosis should not be oversimplified. The interconnection between the gut, the immune system, and the peripheral tissues is complex. The particulars in any given case will be highly individualized.

What this idea can do is open up new avenues for exploring the causes many common, debilitating and seemingly intractable musculoskeletal disorders.

The interval between the first traces of detectable autoantibodies in serum and the manifestations of serious diseases like rheumatoid or osteoarthritis arthritis may be as great as 10 years. This opens opportunities for early interventions during a pre-symptomatic phase, aimed at improving gut barrier function and reducing exposure to food or environmental allergens.

"Screening for predictive autoantibodies could one day become routine," Dr. Larson suggested.

Dr. Larson's lectures on Autoimmunity in Bone & Joint Disease, and Autoimmunity in the Thyroid, Adrenals and Reproductive Organs are part of a comprehensive six-part online video course entitled, Autoimmune Reactivity: Using Predictive Antibody Testing to Improve Clinical Outcomes in Chronic Disease. Available at HPC's new Holistic Education Exchange, the course also features Drs. Aristo Vojdani and Thomas Alexander. The course is supported by an unrestricted educational grant from Cyrex Laboratories.

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