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PPM Commentary: Gum Bacteria Now Linked to RA

New research into a possible pathogen for RA could have significant implications on how researchers now understand the events that lead to RA developing in the body.

In a recent study, investigators at Johns Hopkins published results suggesting a certain type of bacteria implicated in gum disease could be linked to the pathology of rheumatoid arthritis (RA).1 The study could have significant implications on how researchers now understand the events that lead to RA developing in the body. 

Periodontitis (PD) is an inflammatory disease initiated by a bacterial biofilm on teeth. Characterized by the degradation of the tooth-supporting tissues, PD usually progresses slowly among adults and rapidly in young patients. Aggregatibacter actinomycetemcomitans is strongly associated with the aggressive forms of the disease.2,3 Although it has been theorized that bacteria are involved in the pathogenesis of RA, only recently has the link been established.4

In a recent interview with Practical Pain Management, lead author of the study Felipe Andrade, MD, PhD, commented about the significance of the new findings, as this study marks the first time evidence has been submitted A. actinomycetemcomitans could be a role-player in the pathology of RA. To read the original Practical Pain Management report on the study, click here.

“While our findings suggest that A. actinomycetemcomitans could have a major role in the pathogenesis of RA, this is not the prevailing hypothesis, but a new hypothesis,” Dr. Andrade, who is an associate professor of Medicine at the Johns Hopkins University School of Medicine, told Practical Pain Management. “Indeed, the majority of the research about periodontal disease and RA has been focused on a different bacteria (Porphyromonas gingivalis). It is possible that our work may change this view and move the research in RA toward A. actinomycetemcomitans in the future.”

Could Gum Bacteria Be a Link to RA?

RA is a systemic inflammatory disease characterized by polyarthritis.5 One of many autoimmune diseases, RA is a chronic and progressive inflammatory disease that affects the peripheral joints by causing synovial inflammation due to autoantibodies targeting citrullinated proteins.

Citrullination is the conversion of the amino acid arginine to citrulline via the enzyme peptidylarginine deiminase (PAD).6 PD is characterized by inflammation that affects the supportive tissues of the teeth (eg, gingival attachment and alveolar bone).7 The investigators of the study hypothesized that bacteria involved in PD may activate PADs (which are expressed in high levels in neutrophils of synovial fluid during RA flares).4,8

The idea that gum disease and RA could be linked in some way has been a topic of interest since the early 1900s. But for all these years, the prevailing issue has been understanding how exactly they could be linked, said Dr. Andrade.

“Our study began by searching for common factors that may link periodontal disease and RA. Initial clues came from the study of periodontal samples, where the authors found that a similar process that had previously been observed in the joints of patients with RA was occurring in the gums of patients with periodontal disease.”

As it turns out, “hypercitrullination” was the common denominator. While citrullination is a natural process in everyone, an overactive version is seen in patients suffering from RA, which causes an abnormal accumulation of citrullinated proteins and drives the production of antibodies to fight these proteins, leading to inflammation in the joints, said Dr. Andrade.

A. actinomycetemcomitans is a gram-negative, anaerobic coccobacillus that plays an important role in the pathogenesis of PD.9 A significant increase in the incidence of PD has been observed in patients with chronic, active RA compared to healthy subjects, and the prevalence of RA is higher in PD patients compared to individuals without PD.10

The investigators incubated host neutrophils using different serotypes of A. actinomycetemcomitans and discovered hypercitrullination similar to that in patients with PD and RA. This hypercitrullination, however, did not occur with other PD-associated bacteria (ie, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Fusobacterium nucleatum, Prevotella intermedia) in host neutrophils. Additionally, control neutrophils did not reproduce hypercitrullination either, “demonstrating that hypercitrullination is dependent on both bacterial factors and components of host immune cell.”4

Aggregatibacter actinomycetemcomitans: A Possible Key to Understanding RA

Of the approximately 20 bacterial species identified as periodontal pathogens, A. actinomycetemcomitans is among the most commonly studied periodontopathic bacteria. This periodontopathic bacteria is associated with the pathogenesis of RA in a genetically susceptible host.11

“Among different periodontal bacteria, the study identified that only A. actinomycetemcomitans could trigger hypercitrullination in human white blood cells called neutrophils, the major source of citrullinated proteins in RA. A. actinomycetemcomitans causes hypercitrullination by secretion of a toxin called leukotoxin A (LtxA) that pokes holes in white blood cells as a self-defense strategy to kill host immune cells,” Dr. Andrade said.

LtxA is a key virulence factor produced by A. actinomycetemcomitans, and is linked to the aggressive nature of bone loss seen in subjects with localized aggressive PD.12 LtxA induces neutrophil lysis and extracellular release of hypercitrullinated proteins.13 The mechanism of action is an unregulated calcium influx into neutrophils (via LtxA), which activates PADs. The study (which obtained serum from 196 patients with RA, 109 patients with chronic PD, and 100 healthy controls without PD) illustrated an association between anti-LtxA antibodies with RA (43% vs 11% control; P < 0.0001).4

“Further studies demonstrated that almost half of the patients with RA have evidence of infection by A. actinomycetemcomitans, compared with 11% of healthy individuals. More strikingly, exposure to A. actinomycetemcomitans was an important factor for production of antibodies to citrullinated proteins in patients with genetic susceptibility to RA,” Dr. Andrade told Practical Pain Management.

An article by Konig et al illustrates how this periodontal pathogen and its production of LtxA is the link between PD and RA.4 Understanding how and where the disease is initiated can improve treatment strategies. The article also presents an opportunity for further interprofessional collaboration to better prevent or delay onset of RA in susceptible individuals.

Granted, similar parallel efforts are being made to also implicate P. gingivalis, another bacteria associated with gum disease, to also be an inducer of citrullinated proteins in RA. However, according to Dr. Andrade, all of his team’s efforts to corroborate such a link failed. “Our frustration working with P. gingivalis drove the effort to better understand the potential role of other periodontal pathogens in RA,” which is what led them to A. actinomycetemcomitans. “About 50% of the study participants who had RA had no evidence of infection with A. actinomycetemcomitans, which may indicate that other bacteria in the gut, lung, or elsewhere could be using a similar mechanism to induce hypercitrullination. Identifying such bacteria is the next plan for the future,” said Dr. Andrade.

Last updated on: March 1, 2017
Continue Reading:
Bacteria Found in Gum Disease Linked to RA

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