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THE BODY AGAINST ITSELF: BACTERIA INSIDE ONE'S OWN BODY LINKED TO RHEUMATOID ARTHRITIS AND OTHER AUTOIMMUNE DISEASES

ATLANTA - Researchers are using 21st-century technologies to investigate the century-old hypothesis that certain autoimmune diseases, including rheumatoid arthritis, are caused by bacteria living in the human body and will present their initial data this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta.

Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.

Researchers have long associated periodontal disease, or gum inflammation, and bacteria in the gastrointestinal tract with RA, although no specific bacteria have ever been identified by researchers as the bacteria to target as possible therapy. Nevertheless, studies have suggested that bacteria or bacterial products contribute to RA and other autoimmune diseases.

Led by co-principle investigators Steven Abramson, MD, and Dan Littman, MD, PhD, researchers from New York University's Langone Medical Center, aimed to determine whether bacteria in the human mouth and intestines can trigger RA. They used DNA amplification technology to identify what type of bacteria exist in the mouths and intestines of study participants, which included eight people with newly developed RA, three people with psoriatic arthritis, and nine people without these diseases - who were considered healthy.

Previous studies have relied on traditional bacteria cultures, which are only able to identify 20 percent of bacterial species in the human body because of the inability to find the right nutrients to grow the culture, which highlights the uniqueness of this study. "By sending our samples for a deep DNA sequencing, we're able to identify 100 percent of the bacteria that are present," says Jose U. Scher, MD, director of New York University's new Microbiome Center for Rheumatology and Autoimmunity and one of the lead investigators in the study. "So we're taking a huge step forward by not missing 80 percent of the bacteria. Taking that step will allow us to identify bacteria that are related to rheumatoid arthritis."

Although it's too early for this to be applied in the diagnosis of rheumatic diseases in a clinical health care setting, the research is already yielding results that distinguish people with RA from those without. Through this study, researchers were able to identify an over-abundance of the prevotellaceae family of bacteria in the intestinal fecal samples of participants who were newly diagnosed with RA—and had not been treated with drugs for the disease—when compared to those participants in the study who were identified as healthy.

Additionally, researchers found that mouth samples of participants with RA exhibited an overabundance of the porphyromonas genus compared to healthy controls. To examine bacteria in the mouth, researchers studied the gums of participants with RA or psoriatic arthritis, and healthy individuals. When examining the gums of these participants, researchers noted that 78 percent of the examined sites bled during examination in participants with RA, which was a significantly higher percentage than those with psoriatic arthritis (38 percent) and those participants identified as healthy (12 percent). Overall, 66 percent of participants with RA had moderate gum disease - compared to 25 percent of the participants with psoriatic arthritis and 12 percent of the participants in the healthy group.

Additional studies by the group have demonstrated that specific microbes induce the differentiation of Th17 cells in the intestine. There is already strong genetic and therapy-based evidence that pro-inflammatory Th17 cells and anti-inflammatory regulatory T cells (Treg) have critical roles in autoimmune diseases, including RA, psoriatic arthritis, and Crohn's disease.

"The basic premise is that there are different oral and gut bacteria that activate Th17 cells to promote inflammation," Dr. Scher explains. "Our hypotheses are that characterization of Th17-inducing microbes in the human intestine will provide insight into disease pathogenesis, and that directed manipulation of the gut microbiota will result in the alteration of arthritis biomarkers, including Th17/Treg balance."

The next step for the team is a study in which 90 participants with RA will be subdivided into three arms. The first two arms will be given antibiotics for a two-month period, and the third arm will be given placebo. The researchers believe that by modifying the microbial flora with antibiotics, they can identify molecular mechanisms by which RA-associated bacteria affect Th17 and Treg homeostasis and thereby develop new strategies to diminish or even prevent the inflammatory process that leads to chronic destructive arthritis.

The American College of Rheumatology is an international professional medical society that represents more than 8,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Scientific Meeting is the premier meeting in rheumatology. For more information about the meeting, visit www.rheumatology.org/education. Follow the meeting on twitter by using the official hashtag: #ACR2010.

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Editor's Notes: Jose U. Scher, MD will present this research during the ACR Annual Scientific Meeting at the Georgia World Congress Center at 3:30 PM on Tuesday, November 9 in the Room A 411. Dr. Scher will be available for media questions and briefing at 8:30 AM on Monday, November 8 in the on-site press conference room, B 212.

Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care. Also, discover how the ACR Research and Education Foundation's Within Our Reach: Finding a Cure for Rheumatoid Arthritis campaign is accelerating RA research.


Presentation Number: 1390

Characteristic Oral and Intestinal Microbiota in Rheumatoid Arthritis (RA): A Trigger for Autoimmunity?

Jose U. Scher, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Carles Ubeda, PhD
(Memorial Sloan-Kettering Cancer Center, New York, NY)

Michael Pillinger, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Walter Bretz, DDS, DPH
(NYU College of Dentistry, New York, NY)

Yvonne Buischi, DDS, PhD
(NYU College of Dentistry, New York, NY)

Pamela Rosenthal, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Soumya Reddy, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Jonathan Samuels, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Peter Izmirly, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Rennie Howard, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Gary Solomon, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Yusuf Yazici, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Mukundan Attur, PhD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Michele Equinda
(Memorial Sloan-Kettering Cancer Center, New York, NY)

Nicholas Socci,PhD
(Memorial Sloan-Kettering Cancer Center, New York, NY)

Agnes Viale, PhD
(Memorial Sloan-Kettering Cancer Center, New York, NY)

Eric G. Pamer, MD
(Memorial Sloan-Kettering Cancer Center, New York, NY)

Dan R. Littman, MD, PhD
(Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY)

Gerald Weissmann, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Steven B. Abramson, MD
(Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY)

Purpose: The etiology of RA remains unknown, but genetic and environmental factors have been implicated. An infectious trigger has been sought but conventional microbiologic techniques have been uninformative. The human intestine contains a dense, diverse and poorly characterized (≥80% uncultured) bacterial population whose collective genome (microbiome) is ≥100 times larger than its human host. We (DRL) have recently shown in mice that gut-residing bacteria drive autoimmune arthritis via Th17 cell activation (Immunity 2010). Multiple lines of investigation also suggest a link between RA and oral microbes.

Methods: As part of an NIH ARRA grant, the NYU Microbiome Center for Rheumatology and Autoimmunity was established to study gut and oral microbiota in RA and related conditions. A cross-sectional study and prospective proof-of-concept antibiotic intervention trial are ongoing. Fecal samples are collected, periodontal status assessed and oral samples obtained by subgingival biofilm collection. To date, oral/intestinal microbiomes have been analyzed in 8 RA patients, 3 psoriatic arthritis (PsA) patients and 9 healthy controls. Periodontal status was characterized in 30 RA, 4 PsA and 8 controls. DNA was purified and variable 16s rRNA gene regions amplified. PCR products were pyrosequenced (454 Life Sciences), and DNA sequences compared to the RDP and BLAST catalogs. rDNA-based phylogenetic trees were created, and the UNIFRAC metric used to compare bacterial communities across individuals. Sera from all subjects were evaluated for anti-citrullinated peptide antibodies (ACPA).

Results: Prevotellaceae family was significantly overrepresented in fecal microbiota from ACPA+ RA patients (range 13%-85%; mean=38%) vs ACPA- individuals (mean=4.3%); p=0.003. One ACPA+ healthy individual and 1 ACPA+ PsA patient shared similar microbiomes with ACPA+ RA. Subgingival microbiomes in patients with new-onset drug-naive RA exhibited overabundance of the Spirochetaceae / Prevotellaceae / Porphyromonaceae families (mean=53%) compared to chronic-active RA and healthy controls (mean=18.5%). Periodontal assessment revealed 78% of examined sites bled upon probing in RA patients (mean age 39; 73% female), significantly more than controls (38% PsA, 12% healthy; p<0.001 vs="" ra);="" 66%="" of="" ra="" patients="" also="" presented="" with="" moderate="" periodontitis="" compared="" to="" psa="" (25%)="" and="" controls="">

Conclusions: This is the first study using high-throughput technologies to assess oral and intestinal microbiota in RA. Our data corroborate prior reports demonstrating an underappreciated high prevalence of periodontal disease at a young age in patients with RA. Moreover, our preliminary data suggest that ACPA generation may be associated with larger populations of Prevotellaceae in both oral and intestinal microbiomes. In response to such altered microbial flora, certain predisposed individuals may develop auto-inflammatory disease, through mechanisms that may include the generation of cyclic citrullinated peptides or Th17 cell activation in the intestinal mucosa. Thus, the oral and intestinal microbiota merit further investigation as potential triggers for autoimmunity and clinical RA.

Disclosure: Jose Scher, nothing to disclose; Carles Ubeda, nothing to disclose; Michael Pillinger, nothing to disclose; Walter Bretz, nothing to disclose; Yvonne Buischi, nothing to disclose; Pamela Rosenthal, nothing to disclose; Soumya Reddy, nothing to disclose; Jonathan Samuels, nothing to disclose; Peter Izmirly, nothing to disclose; Rennie Howard, nothing to disclose; Gary Solomon, nothing to disclose; Yusuf Yazici, nothing to disclose; Mukundan Attur, nothing to disclose; Michele Equinda, nothing to disclose; Nicholas Socci, nothing to disclose; Agnes Viale, nothing to disclose; Eric Pamer, nothing to disclose; Dan Littman, NIH-NIAMS Grant No. RC2 AR059896: Research grants; Gerald Weissmann, nothing to disclose, Steven Abramson, NIH-NIAMS Grant No. RC2 AR058986: Research grants.

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