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Circulating microbial small RNAs are altered in patients with rheumatoid arthritis
  1. Michelle J Ormseth1,2,
  2. Qiong Wu1,
  3. Shilin Zhao1,
  4. Ryan M Allen1,
  5. Joseph Solus3,
  6. Quanhu Sheng3,
  7. Yan Guo4,
  8. Fei Ye3,
  9. Marisol Ramirez-Solano3,
  10. S Louis Bridges5,
  11. Jeffrey R Curtis6,
  12. Kasey Vickers3,
  13. C Michael Stein1
  1. 1 Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  2. 2 Research & Development, VA Tennessee Valley Healthcare System Nashville Campus, Nashville, Tennessee, USA
  3. 3 Research & Development, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  4. 4 Research & Development, University of New Mexico, Albuquerque, New Mexico, USA
  5. 5 Research & Development, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, USA
  6. 6 Research & Development, University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, USA
  1. Correspondence to Dr Michelle J Ormseth, Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; michelle.ormseth{at}


Objectives To determine if plasma microbial small RNAs (sRNAs) are altered in patients with rheumatoid arthritis (RA) compared with control subjects, associated with RA disease-related features, and altered by disease-modifying antirheumatic drugs (DMARDs).

Methods sRNA sequencing was performed on plasma from 165 patients with RA and 90 matched controls and a separate cohort of 70 patients with RA before and after starting a DMARD. Genome alignments for RA-associated bacteria, representative bacterial and fungal human microbiome genomes and environmental bacteria were performed. Microbial genome counts and individual sRNAs were compared across groups and correlated with disease features. False discovery rate was set at 0.05.

Results Genome counts of Lactobacillus salivarius, Anaerobaculum hydrogeniformans, Staphylococcus epidermidis, Staphylococcus aureus, Paenisporosarcina spp, Facklamia hominis, Sphingobacterium spiritivorum, Lentibacillus amyloliquefaciens, Geobacillus spp, and Pseudomonas fluorescens were significantly decreased in the plasma of RA compared with control subjects. Three microbial transfer RNA-derived sRNAs were increased in RA versus controls and inversely associated with disease activity. Higher total microbial sRNA reads were associated with lower disease activity in RA. Baseline total microbial sRNAs were threefold higher among patients who improved with DMARD versus those who did not but did not change significantly after 6 months of treatment.

Conclusion Plasma microbial sRNA composition is altered in RA versus control subjects and associated with some measures of RA disease activity. DMARD treatment does not alter microbial sRNA abundance or composition, but increased abundance of microbial sRNAs at baseline was associated with disease activity improvement at 6 months.

  • arthritis
  • rheumatoid
  • antirheumatic agents
  • inflammation

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  • Handling editor Josef S Smolen

  • Collaborators TETRAD Investigators: Clifton O, BinghamMarc C, LevesqueLarry W, MorelandPeter A, NigrovicJames R, O’DellNancy Ann Shadick E, William St Clair.

  • Contributors Conception and design of the study: MJO, QW, QS and CMS. Acquisition of data/data analysis: MJO, QW, SZ, RMA, JS, QS, YG, FY, RMA, SLB, JRC, KV, CMS, TETRAD investigators. Drafting of article or revising it critically for important intellectual content: MJO, QW, SZ, RMA, JS, QS, YG, SLB, JRC, KV and CMS. Final approval of the version of the article to be published: all authors.

  • Funding This work is supported by Veterans Health Administration CDA IK2CX001269, Arthritis Foundation Delivering on Discovery grant, Alpha Omicron Pi, NIH grants: P60AR056116 and CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences.

  • Disclaimer Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

  • Competing interests MJO reports grants from Veterans Health Administration/ Office of Research and Development, during the conduct of the study. QW reports grants from Alpha Omicron Pi, during the conduct of the study. CMS reports grants from NIH, during the conduct of the study. TETRAD Investigators: Levesque reports other from Abbvie, outside the submitted work. Shadick reports Brigham and Women’s Hospital grant funding from Mallinckrodt, Bristol Myers Squibb, Crescendo Biosciences, Sanofi-Regeneron, Lilly and AMGEN; consulting for Bristol Myers Squibb.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval The Institutional review board of Vanderbilt University Medical Center approved this study. Additionally, Institutional review boards of University of Alabama at Birmingham, Brigham and Women’s Hospital, Duke University, Johns Hopkins University, North Shore Medical Center, Stanford University, University of Colorado Denver, University of Nebraska, and University of Pittsburgh approved the prospective component of the study. Both studies were approved by each respective university Institutional Review Board (ID# 000567, 150544).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information. Data will be made available on request to the corresponding author (MJO).