Team: Enolase & RA, aka “P. gingivalis and RA”
Region: Ab Workout
Base Article: Lundberg K, Kinloch A, Fisher BA, et al. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 2008;58(10):3009-3019. doi:10.1002/art.23936. PMID 18821669.
Authors: University of South Florida Rheumatology Fellowship. Caroline Bresnan, MD, first year rheumatology fellow, Anastasiya Bagrova, MD, second year rheumatology fellow, Vanessa Osting, DO, MPH, FACR, Assistant Chief of Ambulatory Care Outpatient Services – James A. Haley VA Hospital, Joanne Valeriano-Marcet, MD, Rheumatology program director, Larry Young, MD, Chief of Rheumatology, James A. Haley VA Hospital.
Connections between rheumatologic diseases and human pathogens have been speculated about for decades. Rheumatoid arthritis (RA) was once thought to be caused by a streptococcal infection akin to rheumatic fever1,4. This led to the development of sulfasalazine as a combination antibacterial and anti-inflammatory drug:2 the dream team of medications at the time! Although this connection was disproved, the complex interplay of human genes and the environment, particularly in response to bacterial infection or colonization remains an area of intensive research to identify triggers of autoimmunity.
In the late 1990s, a team of Dutch researchers found the anti-citrullinated peptide antibody to be a highly specific autoantibody in RA, and subsequently developed the anti-CCP ELISA test3. Anti-CCP is one of the MVPs when it comes to RA diagnosis and prognosis. However, the origins of this autoantibody remained unclear.
To elucidate where antibodies to citrullinated peptides may come from, Lundberg et al (2008) examined the relationship between the oral bacterium Porphyromonas gingivalis (a cause of adult periodontitis) and RA. Patients with periodontitis are four times more likely to develop RA than the general population, which is truly a flagrant foul on the bacteria’s part. The authors identified the citrullinated protein a-enolase, which is found in the synovial fluid of RA patients, as a target of anti-citrullinated peptide antibodies. Interestingly, a-enolase is a highly conserved protein and is also made by P. gingivalis. Furthermore, P. gingivalis is the only human pathogen which produces an enzyme peptidyl arginine deaminase (PAD) that is responsible for citrullinating peptides. Our immune cells then target (or double-team, if you will) these citrullinated peptides with antibodies, thus creating a vicious cycle of chronic inflammation and potential for autoimmunity. To demonstrate that bacterial citrullinated peptides may be important in human RA, the researchers collected serum from RA patients, along with disease controls (Sjogren’s, SLE, and spondylarthritis, etc.), and healthy controls. They identified several forms of citrullinated a-enolase (CEP) to mix with the patient sera and found that 64% of RA patients, compared to 15% of controls had antibodies to the CEPs. The form of CEP to which the RA patient’s antibodies bound the most in this study was highly similar to that of P. gingivalis. They subsequently found that antibodies that reacted to the human enolase were cross-reactive to P. gingivalis enolase. These findings suggest that P. gingivalis promotes the development of anti-CCP positive RA by stimulating production of autoantibodies to human citrullinated a-enolase. This was the first study to identify a commensal bacterium as potentially contributing to pathogenesis in RA.
Impact on Rheumatology
This article was excitedly suggested by one of our attendings who clearly remembered hearing about this study during ACR as a fellow. The major impact from the article are not the findings themselves, although also important. It is the fact that this article suggested the role of commensal bacteria in the pathogenesis of autoimmune diseases. It was one of the first articles examining the role of microbiome in rheumatic disease. In the more recent years, microbiome dysregulation has been implicated in IBD, SLE, spondyloarthritis, even APLS5. The role of fecal microbiota transplant is currently being studied in several autoimmune diseases6,7. While we have not yet reached the game changing state of being able to “fix” the abnormal microbiome to cure autoimmune disease, it is a very promising area of research for clinicians and patients. We bet every rheumatologist reading this report gets asked by their patients whether they can be cured with diet, supplements, or life-style modifications. Our paper gives a basis for advice about defensive moves, such as dental care, and provides hope that in the future we will be able to change the pace of play with a prescription for a diet instead of csDMARDs or biologics (not to mention, send the insurance companies and their “preferred medication lists” back to the bench forever).
Chances in the Tournament
We admit we are the dark horse of the tournament. While there are some truly five-star players masterfully crafting their game around us, we believe that our team is a top prospect for a come-from-behind, game-winning, three-pointer at the buzzer. What sets our article apart from the top seeded teams in our bracket is that our article takes a step back from just identifying pathogenic antibodies as a sole player, and examines pathogenesis of the disease itself. Furthermore, as discussed above, our article’s findings have far-reaching implications that can transcend the game by showing the role of microbiome in rheumatic disease and offer targets for cure and prevention.
Next scouting report: Pathogenic ANCA
Back to the full list of scouting reports.
See the Q&A on theMednet.org for the Ab Workout Region: How do you approach follow up in patients with isolated positive ANA, but no current clinical signs or symptoms of systemic lupus erythematosus?
- Benedek TG. The history of bacteriologic concepts of rheumatic fever and rheumatoid arthritis. Semin Arthritis Rheum. 2006 Oct;36(2):109-23. doi: 10.1016/j.semarthrit.2006.05.001. Epub 2006 Jul 13. PMID: 16884972.
- Pinals RS. History of enteric coated sulfasalazine in rheumatoid arthritis. J Rheumatol Suppl. 1988 Sep;16:1-4. PMID: 2903922.
- Schellekens, G.A., Visser, H., De Jong, B.A.W., Van Den Hoogen, F.H.J., Hazes, J.M.W., Breedveld, F.C. and Van Venrooij, W.J. (2000), The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis & Rheumatism, 43: 155-163.
- Svartz N. The origin of rheumatoid arthritis. Rheumatology. 1975;6:322-8. PMID: 1105749.
- Clemente, J. C., Manasson, J., & Scher, J. U. (2018). The role of the gut microbiome in systemic inflammatory disease. Bmj, 360.
- Huang, C., Yi, P., Zhu, M., Zhou, W., Zhang, B., Yi, X., … & Lu, Q. (2022). Safety and efficacy of fecal microbiota transplantation for treatment of systemic lupus erythematosus: An EXPLORER trial. Journal of Autoimmunity, 102844.
- Stoll, M. L. (2022). Therapeutic alteration of the microbiota in rheumatic diseases: Hype or potential?. Best Practice & Research Clinical Rheumatology, 101806.