Published: Apr 16, 2014 | Updated: Apr 17, 2014
By Nancy Walsh, Senior Staff Writer, MedPage Today

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Action Points

For instance, in the Sept. 12, 1900 issue of The Clinical Journal, British physician William Hunter published an influential lecture entitled “Oral sepsis as a cause of disease, with illustrative cases.”

The result? A standard treatment for rheumatoid arthritis (RA) for decades was complete dental extraction, or “therapeutic edentulation.”

The result? A standard treatment for rheumatoid arthritis (RA) for decades was complete dental extraction, or “therapeutic edentulation.”

This practice fell out of favor eventually because of a complete lack of symptomatic relief, and was largely forgotten.

But today, with the concept of the microbiome as an integral contributor to health and disease, the oral cavity, along with other mucosal sites, has once again become a source of attention among researchers. Just a decade ago, Gerald Weissmann, MD, professor emeritus of medicine at New York University, hypothesized that a humoral immune response to the oral bacterium Porphyromonas gingivalis could be an environmental trigger for RA.

The Periodontium as Source?

Considerable evidence has now accrued implicating the periodontium, although debate continues. Various epidemiologic studies have suggested a high frequency and greater severity for periodontal disease among patients with RA, but some have argued that this is an extra-articular manifestation of disease.

However, support for periodontal disease as a trigger has been growing, particularly because antibodies to P. gingivalis have been identified in patients with longstanding RA, and mechanisms by which this pathogen could act are being identified.

“Porphyromonas gingivalis is the only prokaryote known to possess a peptidylarginine deiminase (PAD) enzyme which citrullinates proteins and thus may play a role in the generation of anti-citrullinated protein antibodies (ACPA),” explained Sheila L. Arvikar, MD, of Harvard Medical School.

Citrullination of proteins is a process in which the amino acid arginine residues are catalyzed to citrulline, which then can be attacked by the immune system.

“P. gingivalis may citrullinate self or host proteins. Unlike human PAD, which citrullinates internal arginines, the P. gingivalis PAD enzyme may preferentially citrullinate C-terminal resides, creating neoepitopes,” Arvikar explained to MedPage Today.

“These neoepitopes may stimulate production of ACPA autoantibodies, which are highly specific biomarkers in RA,” she said.

The ACPA autoantibodies have been detected before the onset of RA symptoms, which has further supported a role in disease pathogenesis, and the end result of the P. gingivaliscitrullination process could be the triggering of autoimmunity.

Correlation With Disease?

While antibody responses to P. gingivalis have been seen in some previous studies among patients with advanced RA, whether or not these antibodies participate in early disease or correlate with disease has been unknown.

Therefore, Arvikar and her colleagues enrolled 50 patients with new-onset, untreated RA, and found that one-third of them had positive IgG antibodies to the pathogen at baseline.

Compared with healthy controls, the frequency and level of antibodies were significantly higher in the RA patients. The antibodies also were more common in RA patients than in patients with other autoimmune and connective tissue disorders.

The antibody responses also correlated with disease markers. For instance, at baseline 88% of RA patients who were positive for the P. gingivalis antibodies also had elevated levels of ACPA. In addition, the antibody-positive patients were more likely to be rheumatoid factor positive and to have high erythrocyte sedimentation rates.

Furthermore, P. gingivalis-positive patients had higher scores for dysfunction, and “the degree of dysfunction correlated directly with the magnitude of [P. gingivalis] antibody reactivity (r=0.3, P=0.05), Avrikar’s group reported online in Arthritis Research & Therapy.

The researchers then followed the patients for a year, during which time all received disease-modifying anti-rheumatic drug treatment. At the 12-month follow-up visit, antibody-positive patients tended to have worse disease. Only 38% of the antibody-positive group were in remission at that point compared with 64% of the antibody-negative group.

“These findings are consistent with a role for [P. gingivalis] in disease pathogenesis in a subset of RA patients,” they concluded.

Could It Be the Lung?

A group of researchers at the University of Colorado led by Kevin D. Deane, MD, PhD, have raised the additional possibility of the lung as another possible site for RA disease initiation.

“The lungs made a lot of sense to us. A lot of stuff from the environment comes in to the lung where the immune system has to deal with it. We know that mucosal surfaces have the immune machinery present to be able to mount immune responses, and it’s not a big step to think that could go bad and cause autoimmunity,” Deane said in an interview.

To explore this possibility, his group first evaluated a group of 42 individuals who were considered to be at risk for RA because of ACPA positivity, although they were without joint symptoms, as well as 12 patients with established seropositive early RA and 15 seronegative controls.

On high-resolution CT, three-quarters of the at-risk individuals had some type of airway abnormality such as thickening of the bronchial wall and centrilobular opacities, similar to what was seen in the early established RA group, compared with only one-third of the seronegative controls.

“Airways abnormalities in RA-related autoantibody-positive individuals without apparent inflammatory arthritis suggest that the lung is an early target, or potentially a site of initial generation, of RA-related autoimmunity,” Deane and colleagues wrote in Arthritis & Rheumatism.

They then sought more direct evidence of autoantibody generation in the lung by conducting induced sputum tests in 49 individuals considered to be at risk because of seropositivity for ACPA or rheumatoid factor or a family history, as well as in 14 patients with early RA and 21 healthy controls.

They detected at least one RA-associated autoantibody in the sputum of 39% of individualswith a family history of RA, in 65% of those who were seropositive, and in 86% of patients with established RA.

“It is possible that our findings of elevated RA-related autoantibodies in induced sputum, which preferentially samples the mucosal milieu of the bronchial tree, reflects underlying generation of RA-related autoimmunity within the airways,” Deane’s group wrote, again inArthritis & Rheumatism.

The Million Dollar Question

As to the key uncertainty of how infection in the gums or antibody generation in the lungs could lead to disease manifestations in the joint, Arvikar commented, “This is the million dollar question, which I don’t think anyone can answer at this point.”

“One theory is that the oral pathogens could directly infect joints. Although some studies have shown detection of DNA from P. gingivalis pathogens in joints, it seems unlikely that anaerobes such as P. gingivalis could survive transit through the bloodstream and survive within the joint,” she said.

“Rather, it may be that local production of citrullinated neoepitopes triggers formation of ACPA. The subsequent steps in the transition from systemic autoimmunity to joint inflammation are not well understood, but may involve shared antigenic targets between oral mucosa and joints, and epitope spreading leading to the formation of autoantibodies against proteins found within the joint,” she suggested.

Inflammation itself also may contribute to the process.

“It could be that inflammation from bacteria causes changes in our own tissue, which then becomes a target for the immune system,” Deane said.

In addition, the immune response can evolve over time, shifting from one target tissue to another, according to Deane.

“We also know that immune cells and proteins move around in the body, and the joints are particularly susceptible to things that flow through the blood and pile up. That’s why when you get the flu you can have aches and pains in your joints, because of immune debris building up,” he explained.

What’s Next?

An additional site that has been proposed is the gut, where an alteration of commensal bacteria has been identified in patients with RA.

“I think different people might have different sites, with some having the gums, others the lungs, and still others the gut mucosa,” Deane said.

More translational and clinical research will be needed to fully understand the relationship between the microbiome and autoimmunity.

“One area would be looking at the microbial composition of multiple mucosal sites in the same patient to understand the contribution of each site,” Arvikar noted.

“Prospective studies following the microbiome in high-risk individuals serially through diagnosis and treatment are also needed,” she said.

Interventions against P. gingivalis or to alter the microbiome “may also help to strengthen evidence of a connection,” she concluded.

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