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Evidence that at least some forms of rheumatoid arthritis (RA) are connected to the intestinal microbiome continues to mount, with a new study showing that antibodies to a common intestinal bacterium appear elevated throughout the spectrum of disease.

Individuals diagnosed with RA had higher median levels of IgA antibodies to than did matched non-RA controls (OR 1.44, P=0.01), and there was a modest trend in that direction for people not yet diagnosed but testing positive for an RA-related biomarker, according to Jennifer Seifert, MPH, of the University of Colorado in Aurora, and colleagues.

When the RA patients were stratified by duration of disease (≤1 year from diagnosis vs more than 1 year), anti-P. copri antibody titers were numerically higher for both subgroups relative to matched controls, significantly so for the "established" RA group (OR 1.42, P=0.03), the investigators reported in . The study was perhaps underpowered for these subgroup analyses, with only 165 participants overall in the RA and at-risk groups, and barely two dozen with early RA.

It's not the first study to link P. copri with RA -- researchers were a decade ago. That RA patients were more likely to show antibodies to this organism was among the earliest findings. The new study now extends the linkage to patients in the earliest stages of the disease, including, at least tentatively, to what might be termed "pre-RA."

RA patients were drawn from a . A total of 98 RA patients were included, of whom 27 were 1 year or less from diagnosis. Seifert and colleagues also identified 67 at-risk individuals in the community (via recruitment from clinics and local events), with this status defined as seropositivity for antibodies to cyclic citrullinated peptide-3 (anti-CCP3). One-third of these participants were first-degree relatives of RA patients. RA patients were included in the analysis irrespective of anti-CCP3 status.

For each RA patient and at-risk participant, the researchers enrolled an age- and sex-matched control recruited in the community through advertisements and at health fairs.

In addition to anti-P. copri IgA antibodies, Seifert and colleagues also examined IgG antibodies to the bacterium. Their titers followed the same pattern as was seen with IgA but less strongly, such that none of the associations reached statistical significance. Dot plots also revealed substantial scatter within subgroups -- for some comparisons, it appeared that a few outliers were driving the differences.

How might immune responses to intestinal flora cause or contribute to a joint disease? Seifert and colleagues did not claim to have a definitive answer, but they pointed to "sequence homology" between Prevotella antigens and certain synovial tissue proteins. Antibodies to the former might cross-react with the latter to trigger chronic inflammation, the researchers suggested.

"Further investigation into the roles of [P. copri] and other microorganisms in RA evolution and pathogenesis of disease is warranted," the researchers concluded. "Such knowledge may lead to the development of therapies targeting immunogenic bacterial commensals and/or pathobionts, which may prevent the development of RA in at-risk individuals and may have a beneficial effect in those with new-onset or established RA."

Limitations to the study, besides the small numbers of participants, included use of a single antibody species (targeting one particular bacterial antigen) to define at-risk status, and that the analysis did not take account of possible microbiome alterations from RA patients' use of immunomodulating therapies.

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