The intestinal microbiome "is vast and diverse. It contains 100 times more protein-coding genes than the human genome, and harbors 100 trillion cells, 10-fold the amount of total host human cells," wrote New York University researchers Dr. Jose U. Scher and Dr. Steven B. Abramson recently (Arthritis Res. Ther. 2013;15:122). "Virtually all studies consistently report only a small fraction of RA patients as being exposed to P. gingivalis." It is "plausible" that changes in the microbial composition at several mucosal sites is required for progression to RA, they wrote.
"The largest amount of recent evidence related to a specific species of bacteria and the etiology of RA has been for periodontal disease and P. gingivalis, but there have been many other investigations that focused on other factors and other mucosal sites, including the lung, gastrointestinal, and genitourinary mucosal surfaces," said Dr. M. Kristen Demoruelle, a rheumatologist at the University of Colorado in Aurora. "There are some very interesting data for P. gingivalis, especially the finding that it has an enzyme capable of citrullinating human proteins. However, other findings showed P. gingivalis was not specifically associated with RA, and studies of other mucosa sites such as the GI tract found other bacteria – not P. gingivalis – associated with RA. Overall, P. gingivalis and the gingival mucosa may play an important role in the etiology of RA in some people, but in many other people, other factors and other musocal sites are likely involved," she said in an interview.
Dr. M. Kristen Demoruelle
The field "is still in its infancy and struggling to figure out the best way forward," cautioned Dr. Molitor. The range of possible mucosal sites and their microbiome diversity produce findings that are "complex and confusing," he said. "I am almost certain that no single study will provide a giant breakthrough, that this is the one bacterial species that is the major risk for RA and all we need to do is use one antibiotic to prevent it." Despite that, "the driving force behind this research remains the idea of preventing RA."
"I’d like to have a better understanding of the complex environment [of the oral mucosa] and the mechanisms involved in RA association, but early studies of intervention are probably warranted," said Dr. Mikuls.
"I think there is sufficient evidence to support" an intervention trial, agreed Dr. Arvikar. "Treatment of periodontal disease does not carry much risk, and it arguably is the standard of care."
She cited a periodontal disease intervention trial launched in France that enrolled 40 patients with RA and periodontal disease that was designed to assess the impact of periodontal treatment on RA. Another intervention run by Dr. Scher and Dr. Abramson from NYU randomized about 180 people with RA, psoriatic arthritis, or controls without arthritis to treatment with doxycycline, vancomycin, or placebo. Both studies were scheduled for completion during 2013.
Dr. Sheila L. Arvikar
"A key question is whether bacteria such as P. gingivalis are a cause or effect of RA. The main clinical application will be if a specific bacterium is identified to be causal. Then it could be directly targeted in treatment. And if a specific bacterium is associated with development of preclinical RA-related autoimmunity it may be a biomarker to identify future RA risk," Dr. Demoruelle said. "We still need to know the best time to target these bacteria. If bacteria trigger disease prior to the first symptoms, we’ll need to have ways to find these people."
With a deeper understanding of mucosal-surface microbiomes as well as contributing genetic factors "we may be able to design a reasonable, pre-disease intervention trial for people at very high risk, see if we can step in early and stop progression before it gets to where it results in full-blown RA," said Dr. Molitor.
Dr. Molitor, Dr. Mikuls, Dr. Arvikar, and Dr. Demoruelle said that they had no disclosures.
On Twitter @mitchelzoler